Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
c.dna | Variant | SGM Consensus | Domain | ClinVar | gnomAD | ESM1b | AlphaMissense | REVEL | FoldX | Rosetta | Foldetta | PremPS | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | DOI | |||||||||||||||||||||||||||||||||
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Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Score | Prediction | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | PAM250 | PAM120 | Hydropathy Δ | MW Δ | Average | Δ | Δ | StdDev | Δ | StdDev | Secondary | Tertiary bonds | Inside out | GAP-Ras interface | At membrane | No effect | MD Alert | Verdict | Description | |||||
c.3614T>C | L1205P![]() | Likely Pathogenic | Coiled-coil | Uncertain | 1 | -16.878 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.536 | Likely Pathogenic | -5.91 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.45 | Pathogenic | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||
c.3631A>G | M1211V![]() | Likely Benign | Coiled-coil | Benign | 1 | 6-33446623-A-G | 3 | 1.86e-6 | -2.101 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.412 | Likely Benign | -0.29 | Neutral | 0.932 | Possibly Damaging | 0.949 | Probably Damaging | 5.43 | Benign | 0.72 | Tolerated | 3.77 | 5 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||
c.3632T>A | M1211K![]() | Likely Pathogenic | Coiled-coil | Likely Benign | 1 | -9.013 | Likely Pathogenic | 0.662 | Likely Pathogenic | Likely Benign | 0.595 | Likely Pathogenic | -2.95 | Deleterious | 0.987 | Probably Damaging | 0.979 | Probably Damaging | 5.59 | Benign | 0.01 | Affected | 3.77 | 5 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
c.3633G>A | M1211I![]() | Likely Benign | Coiled-coil | Uncertain | 1 | 6-33446625-G-A | 3 | 1.86e-6 | -1.537 | Likely Benign | 0.764 | Likely Pathogenic | Likely Benign | 0.298 | Likely Benign | -0.42 | Neutral | 0.969 | Probably Damaging | 0.968 | Probably Damaging | 5.40 | Benign | 1.00 | Tolerated | 3.77 | 5 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||
c.3635C>T | S1212F![]() | Likely Pathogenic | Coiled-coil | Conflicting | 2 | -14.445 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.271 | Likely Benign | -4.52 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.03 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
c.3638A>C | N1213T![]() | Likely Benign | Coiled-coil | Conflicting | 2 | 6-33446630-A-C | 46 | 2.85e-5 | -5.428 | Likely Benign | 0.266 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.08 | Neutral | 0.959 | Probably Damaging | 0.721 | Possibly Damaging | 2.74 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||
c.3638A>G | N1213S![]() | Likely Benign | Coiled-coil | Benign | 1 | 6-33446630-A-G | 13 | 8.05e-6 | -4.086 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -0.56 | Neutral | 0.906 | Possibly Damaging | 0.551 | Possibly Damaging | 2.82 | Benign | 0.68 | Tolerated | 3.77 | 5 | 1 | 1 | 2.7 | -27.03 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||
c.3640C>T | R1214W![]() | Likely Pathogenic | Coiled-coil | Uncertain | 1 | 6-33446632-C-T | 2 | 1.24e-6 | -8.799 | Likely Pathogenic | 0.710 | Likely Pathogenic | Likely Benign | 0.143 | Likely Benign | -4.95 | Deleterious | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||
c.3653A>T | E1218V![]() | Likely Pathogenic | Coiled-coil | Uncertain | 2 | -5.647 | Likely Benign | 0.936 | Likely Pathogenic | Ambiguous | 0.418 | Likely Benign | -5.68 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.21 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
c.3655T>C | Y1219H![]() | Likely Pathogenic | Coiled-coil | Uncertain | 1 | -9.511 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.363 | Likely Benign | -3.62 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.15 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
c.3661C>T | R1221W![]() | Likely Pathogenic | Coiled-coil | Conflicting | 3 | 6-33446653-C-T | 1 | 6.20e-7 | -10.938 | Likely Pathogenic | 0.651 | Likely Pathogenic | Likely Benign | 0.174 | Likely Benign | -4.57 | Deleterious | 1.000 | Probably Damaging | 0.987 | Probably Damaging | 2.50 | Benign | 0.01 | Affected | 3.77 | 5 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||
c.3662G>A | R1221Q![]() | Likely Benign | Coiled-coil | Conflicting | 2 | 6-33446654-G-A | 4 | 2.48e-6 | -5.491 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.46 | Neutral | 0.836 | Possibly Damaging | 0.153 | Benign | 2.56 | Benign | 0.12 | Tolerated | 3.77 | 5 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||
c.3686A>C | Q1229P![]() | Likely Pathogenic | Coiled-coil | Uncertain | 1 | -10.397 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.422 | Likely Benign | -3.69 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 1.75 | Pathogenic | 0.12 | Tolerated | 3.77 | 5 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
c.36C>G | S12R![]() | Likely Benign | Uncertain | 1 | 6-33420300-C-G | 4 | 2.59e-6 | -4.033 | Likely Benign | 0.500 | Ambiguous | Likely Benign | 0.097 | Likely Benign | -0.30 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||
c.3705G>A | M1235I![]() | Likely Benign | Coiled-coil | Uncertain | 1 | -4.312 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.027 | Likely Benign | -1.44 | Neutral | 0.139 | Benign | 0.056 | Benign | 2.69 | Benign | 0.04 | Affected | 3.77 | 5 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
c.371C>T | A124V![]() | Likely Benign | Conflicting | 2 | 6-33432236-C-T | 9 | 5.58e-6 | -4.259 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.073 | Likely Benign | -1.52 | Neutral | 0.173 | Benign | 0.009 | Benign | 4.07 | Benign | 0.03 | Affected | 3.61 | 5 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||
c.3731G>A | S1244N![]() | Likely Pathogenic | Coiled-coil | Uncertain | 1 | -9.008 | Likely Pathogenic | 0.751 | Likely Pathogenic | Likely Benign | 0.154 | Likely Benign | -1.87 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.10 | Pathogenic | 0.15 | Tolerated | 3.77 | 5 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||
c.373C>T | P125S![]() | Likely Benign | Uncertain | 1 | -3.769 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -3.57 | Deleterious | 0.580 | Possibly Damaging | 0.140 | Benign | 2.86 | Benign | 0.02 | Affected | 3.61 | 5 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
c.3773A>G | Q1258R![]() | Likely Pathogenic | Coiled-coil | Uncertain | 1 | -10.971 | Likely Pathogenic | 0.931 | Likely Pathogenic | Ambiguous | 0.316 | Likely Benign | -3.19 | Deleterious | 0.994 | Probably Damaging | 0.988 | Probably Damaging | 2.00 | Pathogenic | 0.00 | Affected | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||
c.3788T>C | I1263T![]() | Likely Pathogenic | Coiled-coil | Uncertain | 1 | 6-33446780-T-C | 2 | 1.24e-6 | -6.564 | Likely Benign | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.529 | Likely Pathogenic | -4.15 | Deleterious | 0.946 | Possibly Damaging | 0.673 | Possibly Damaging | 1.81 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0 | -1 | -5.2 | -12.05 | ||||||||||||||||||||||||||
c.3794G>C | R1265T![]() | Likely Pathogenic | Coiled-coil | Likely Pathogenic | 1 | -10.129 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.529 | Likely Pathogenic | -4.97 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||
c.37A>G | I13V![]() | Likely Benign | Uncertain | 1 | -2.497 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.110 | Likely Benign | 0.01 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.25 | Benign | 0.00 | Affected | 4 | 3 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||||
c.3806T>A | V1269E![]() | Likely Pathogenic | Coiled-coil | Uncertain | 1 | -11.418 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.403 | Likely Benign | -5.05 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.09 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
c.380G>A | R127Q![]() | Likely Benign | Uncertain | 1 | 6-33432245-G-A | 6 | 3.72e-6 | -1.711 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.037 | Likely Benign | -1.04 | Neutral | 0.006 | Benign | 0.001 | Benign | 4.04 | Benign | 0.02 | Affected | 3.74 | 4 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
c.3820C>T | R1274C![]() | Uncertain | 1 | 6-33447868-C-T | -6.467 | Likely Benign | 0.439 | Ambiguous | Likely Benign | 0.170 | Likely Benign | -5.22 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.46 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -4 | -3 | 7.0 | -53.05 | ||||||||||||||||||||||||||||||
c.3821G>A | R1274H![]() | Likely Benign | 1 | 6-33447869-G-A | 4 | 2.58e-6 | -5.259 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -3.20 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0 | 2 | 1.3 | -19.05 | ||||||||||||||||||||||||||||
c.3824G>A | R1275Q![]() | Likely Benign | Uncertain | 1 | 6-33447872-G-A | 2 | 1.29e-6 | -4.928 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -1.72 | Neutral | 0.898 | Possibly Damaging | 0.147 | Benign | 2.59 | Benign | 0.03 | Affected | 3.77 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
c.3824G>T | R1275L![]() | Likely Benign | 1 | 6-33447872-G-T | 1 | 6.45e-7 | -6.052 | Likely Benign | 0.446 | Ambiguous | Likely Benign | 0.117 | Likely Benign | -4.04 | Deleterious | 0.800 | Possibly Damaging | 0.277 | Benign | 2.55 | Benign | 0.01 | Affected | 3.77 | 5 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||
c.382C>A | P128T![]() | Likely Benign | Uncertain | 1 | 6-33432247-C-A | 1 | 6.20e-7 | -4.217 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.96 | Neutral | 0.952 | Possibly Damaging | 0.500 | Possibly Damaging | 4.19 | Benign | 0.35 | Tolerated | 3.74 | 4 | -1 | 0 | 0.9 | 3.99 | |||||||||||||||||||||||||||
c.3835G>A | A1279T![]() | Likely Benign | Uncertain | 2 | 6-33447883-G-A | 2 | 1.29e-6 | -4.871 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -0.30 | Neutral | 0.001 | Benign | 0.000 | Benign | 2.71 | Benign | 0.09 | Tolerated | 3.77 | 5 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||
c.3846G>C | E1282D![]() | Likely Benign | Uncertain | 1 | 6-33447894-G-C | 1 | 6.44e-7 | -3.879 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.26 | Neutral | 0.112 | Benign | 0.036 | Benign | 2.70 | Benign | 0.39 | Tolerated | 3.77 | 5 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||
c.3848C>T | P1283L![]() | Likely Benign | Benign | 1 | 6-33447896-C-T | 32 | 2.06e-5 | -3.740 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -1.04 | Neutral | 0.005 | Benign | 0.003 | Benign | 2.76 | Benign | 0.06 | Tolerated | 3.77 | 5 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||
c.3858A>T | E1286D![]() | Likely Benign | Conflicting | 4 | 6-33447906-A-T | 143 | 9.22e-5 | -4.010 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.036 | Likely Benign | 1.02 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.96 | Benign | 1.00 | Tolerated | 3.77 | 5 | 3 | 2 | 0.0 | -14.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||
c.3859C>A | P1287T![]() | Likely Benign | Uncertain | 1 | 6-33447907-C-A | -3.940 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.22 | Neutral | 0.126 | Benign | 0.041 | Benign | 2.78 | Benign | 0.04 | Affected | 3.77 | 5 | -1 | 0 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
c.3860C>T | P1287L![]() | Likely Benign | Conflicting | 2 | 6-33447908-C-T | -2.800 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -1.66 | Neutral | 0.021 | Benign | 0.017 | Benign | 2.76 | Benign | 0.02 | Affected | 3.77 | 5 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
c.3862A>G | K1288E![]() | Uncertain | 1 | 6-33447910-A-G | 5 | 3.22e-6 | -2.751 | Likely Benign | 0.407 | Ambiguous | Likely Benign | 0.185 | Likely Benign | -3.27 | Deleterious | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.13 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 1 | 0 | 0.4 | 0.94 | ||||||||||||||||||||||||||||
c.3902C>A | P1301H![]() | Likely Benign | Conflicting | 2 | 6-33451776-C-A | 5 | 3.10e-6 | -5.756 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.232 | Likely Benign | -1.13 | Neutral | 0.642 | Possibly Damaging | 0.378 | Benign | 2.79 | Benign | 0.04 | Affected | 3.77 | 5 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||
c.3902C>G | P1301R![]() | Likely Benign | Uncertain | 1 | 6-33451776-C-G | 15 | 9.30e-6 | -4.753 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.13 | Neutral | 0.077 | Benign | 0.059 | Benign | 2.81 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||
c.3906G>C | L1302F![]() | Uncertain | 1 | -5.674 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.211 | Likely Benign | -2.70 | Deleterious | 0.960 | Probably Damaging | 0.657 | Possibly Damaging | 1.53 | Pathogenic | 0.00 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||
c.3907G>A | G1303S![]() | Likely Benign | Uncertain | 1 | -2.271 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.155 | Likely Benign | -0.19 | Neutral | 0.649 | Possibly Damaging | 0.433 | Benign | 2.84 | Benign | 0.18 | Tolerated | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
c.3913A>G | T1305A![]() | Likely Benign | Conflicting | 4 | 6-33451787-A-G | 30 | 1.86e-5 | -2.692 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 1.74 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.24 | Benign | 1.00 | Tolerated | 3.77 | 5 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||
c.391G>C | G131R![]() | Uncertain | 1 | -6.564 | Likely Benign | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.099 | Likely Benign | -3.82 | Deleterious | 0.983 | Probably Damaging | 0.656 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 3.61 | 5 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||
c.3920C>A | P1307Q![]() | Likely Benign | Uncertain | 1 | 6-33451794-C-A | -4.227 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.192 | Likely Benign | -0.88 | Neutral | 0.988 | Probably Damaging | 0.765 | Possibly Damaging | 2.82 | Benign | 0.03 | Affected | 3.77 | 5 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||
c.3920C>T | P1307L![]() | Likely Benign | Benign | 1 | 6-33451794-C-T | 11 | 6.82e-6 | -4.044 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.292 | Likely Benign | -1.49 | Neutral | 0.779 | Possibly Damaging | 0.220 | Benign | 2.82 | Benign | 0.04 | Affected | 3.77 | 5 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||
c.3922C>T | R1308C![]() | Conflicting | 2 | 6-33451796-C-T | 4 | 2.48e-6 | -4.994 | Likely Benign | 0.421 | Ambiguous | Likely Benign | 0.352 | Likely Benign | -4.89 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 2.31 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -4 | -3 | 7.0 | -53.05 | ||||||||||||||||||||||||||||
c.3923G>A | R1308H![]() | Uncertain | 1 | 6-33451797-G-A | 3 | 1.86e-6 | -3.586 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.319 | Likely Benign | -3.12 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 2.33 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||
c.3929C>T | T1310M![]() | Likely Benign | Benign | 1 | 6-33451803-C-T | 17 | 1.05e-5 | -4.822 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 2.19 | Neutral | 0.021 | Benign | 0.005 | Benign | 2.98 | Benign | 0.93 | Tolerated | 3.77 | 5 | -1 | -1 | 2.6 | 30.09 | |||||||||||||||||||||||||||
c.3932T>C | L1311P![]() | Likely Benign | Likely Benign | 1 | 6-33451806-T-C | 1 | 6.21e-7 | -1.831 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.52 | Neutral | 0.579 | Possibly Damaging | 0.335 | Benign | 2.72 | Benign | 0.18 | Tolerated | 3.77 | 5 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||
c.3941C>T | P1314L![]() | Likely Benign | Likely Benign | 1 | 6-33451815-C-T | 2 | 1.24e-6 | -4.040 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -0.20 | Neutral | 0.421 | Benign | 0.066 | Benign | 4.19 | Benign | 0.05 | Affected | 3.77 | 5 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||
c.3943T>C | W1315R![]() | Likely Benign | Uncertain | 1 | 0.205 | Likely Benign | 0.660 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | 1.31 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.37 | Benign | 0.91 | Tolerated | 3.77 | 5 | 2 | -3 | -3.6 | -30.03 | ||||||||||||||||||||||||||||||
c.3949G>A | G1317S![]() | Likely Benign | Conflicting | 3 | 6-33451823-G-A | 1 | 6.26e-7 | -3.522 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -2.45 | Neutral | 0.127 | Benign | 0.045 | Benign | 4.08 | Benign | 0.00 | Affected | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
c.3956C>G | A1319G![]() | Likely Benign | Uncertain | 2 | 6-33451830-C-G | -3.927 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -0.74 | Neutral | 0.819 | Possibly Damaging | 0.581 | Possibly Damaging | 4.07 | Benign | 0.06 | Tolerated | 3.77 | 5 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
c.3958C>T | P1320S![]() | Likely Benign | Uncertain | 1 | 6-33451832-C-T | 2 | 1.28e-6 | -4.928 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.69 | Neutral | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 4.25 | Benign | 0.00 | Affected | 3.77 | 5 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||
c.3961C>T | P1321S![]() | Likely Benign | Uncertain | 2 | 6-33451835-C-T | 10 | 6.46e-6 | -4.897 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.68 | Neutral | 0.028 | Benign | 0.004 | Benign | 4.27 | Benign | 0.71 | Tolerated | 3.77 | 5 | 1 | -1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||
c.3962C>A | P1321Q![]() | Likely Benign | Benign | 1 | 6-33451836-C-A | 1 | 6.58e-7 | -5.594 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.74 | Neutral | 0.659 | Possibly Damaging | 0.034 | Benign | 4.24 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||
c.3964G>C | A1322P![]() | Likely Benign | Benign | 1 | 6-33451838-G-C | -1.153 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.03 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.15 | Benign | 0.23 | Tolerated | 3.77 | 5 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
c.3970C>T | P1324S![]() | Likely Benign | Likely Benign | 1 | 6-33451844-C-T | 5 | 3.26e-6 | -5.451 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.35 | Neutral | 0.225 | Benign | 0.092 | Benign | 4.33 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||
c.3974C>T | P1325L![]() | Likely Benign | Uncertain | 1 | 6-33451848-C-T | -5.256 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -1.05 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.05 | Benign | 0.00 | Affected | 4.32 | 1 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
c.3977C>A | P1326Q![]() | Likely Benign | Uncertain | 1 | 6-33451851-C-A | 1 | 6.40e-7 | -5.422 | Likely Benign | 0.128 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -0.86 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.62 | Benign | 0.00 | Affected | 3.77 | 5 | -1 | 0 | -1.9 | 31.01 | |||||||||||||||||||||||||||
c.3977C>G | P1326R![]() | Likely Benign | Uncertain | 1 | -5.097 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -0.82 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.62 | Benign | 0.00 | Affected | 3.77 | 5 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||
c.3977C>T | P1326L![]() | Likely Benign | Uncertain | 1 | -5.541 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.06 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.62 | Benign | 0.00 | Affected | 3.77 | 5 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||
c.3979C>T | P1327S![]() | Likely Benign | Uncertain | 1 | 6-33451853-C-T | -4.744 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.28 | Neutral | 0.980 | Probably Damaging | 0.857 | Possibly Damaging | 4.25 | Benign | 0.71 | Tolerated | 3.77 | 5 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
c.3980C>T | P1327L![]() | Likely Benign | Uncertain | 1 | 6-33451854-C-T | 2 | 1.28e-6 | -5.264 | Likely Benign | 0.242 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -1.24 | Neutral | 0.994 | Probably Damaging | 0.908 | Possibly Damaging | 4.12 | Benign | 0.10 | Tolerated | 3.77 | 5 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||
c.3983G>A | R1328Q![]() | Likely Benign | Uncertain | 3 | 6-33451857-G-A | 35 | 1.49e-4 | -2.921 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -1.02 | Neutral | 0.799 | Possibly Damaging | 0.098 | Benign | 4.12 | Benign | 0.03 | Affected | 3.77 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
c.3983G>C | R1328P![]() | Likely Benign | Benign | 1 | 6-33451857-G-C | -1.220 | Likely Benign | 0.466 | Ambiguous | Likely Benign | 0.060 | Likely Benign | -2.01 | Neutral | 0.927 | Possibly Damaging | 0.452 | Possibly Damaging | 4.06 | Benign | 0.01 | Affected | 3.77 | 5 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
c.3995C>T | T1332M![]() | Likely Benign | 1 | 6-33451869-C-T | 20 | 1.86e-5 | -4.107 | Likely Benign | 0.948 | Likely Pathogenic | Ambiguous | 0.252 | Likely Benign | -3.63 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 2.95 | Benign | 0.00 | Affected | 3.77 | 5 | -1 | -1 | 2.6 | 30.09 | ||||||||||||||||||||||||||||
c.3G>A | M1I![]() | Likely Benign | Conflicting | 3 | -5.397 | Likely Benign | 0.227 | Likely Benign | -0.17 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.25 | Benign | 0.00 | Affected | 4.32 | 1 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||
c.4000A>G | N1334D![]() | Uncertain | 1 | 6-33451874-A-G | -4.584 | Likely Benign | 0.674 | Likely Pathogenic | Likely Benign | 0.126 | Likely Benign | -3.06 | Deleterious | 0.886 | Possibly Damaging | 0.522 | Possibly Damaging | 3.55 | Benign | 0.00 | Affected | 3.77 | 5 | 1 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
c.4003G>A | G1335S![]() | Likely Pathogenic | Conflicting | 2 | 6-33451877-G-A | 3 | 2.37e-6 | -4.495 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.362 | Likely Benign | -3.79 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.04 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
c.4006G>A | E1336K![]() | Likely Benign | Benign | 2 | 6-33451880-G-A | 6 | 4.20e-6 | -4.697 | Likely Benign | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.272 | Likely Benign | -2.44 | Neutral | 0.748 | Possibly Damaging | 0.079 | Benign | 3.23 | Benign | 0.00 | Affected | 3.77 | 5 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||
c.4008G>C | E1336D![]() | Likely Benign | Likely Benign | 1 | -3.344 | Likely Benign | 0.596 | Likely Pathogenic | Likely Benign | 0.062 | Likely Benign | -1.92 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.30 | Benign | 0.00 | Affected | 3.77 | 5 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
c.4013G>A | R1338Q![]() | Likely Benign | Conflicting | 3 | 6-33451887-G-A | 12 | 8.40e-6 | -3.494 | Likely Benign | 0.317 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.87 | Neutral | 0.896 | Possibly Damaging | 0.194 | Benign | 3.81 | Benign | 0.02 | Affected | 3.77 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
c.401G>A | S134N![]() | Likely Benign | Uncertain | 1 | -5.534 | Likely Benign | 0.813 | Likely Pathogenic | Ambiguous | 0.075 | Likely Benign | -1.62 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.90 | Benign | 0.00 | Affected | 3.61 | 5 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||
c.4021G>A | A1341T![]() | Likely Benign | Conflicting | 3 | 6-33451895-G-A | 45 | 3.44e-5 | -3.224 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.58 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.03 | Affected | 3.77 | 5 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||
c.4021G>T | A1341S![]() | Likely Benign | Uncertain | 1 | 6-33451895-G-T | -2.867 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.099 | Likely Benign | 0.80 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.40 | Benign | 1.00 | Tolerated | 3.77 | 5 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
c.404G>A | R135Q![]() | Uncertain | 1 | 6-33432701-G-A | 5 | 3.84e-6 | -8.011 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 0.087 | Likely Benign | -1.94 | Neutral | 0.327 | Benign | 0.100 | Benign | 3.76 | Benign | 0.02 | Affected | 3.61 | 5 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||
c.406C>T | R136W![]() | Likely Pathogenic | Uncertain | 2 | -10.453 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.237 | Likely Benign | -4.71 | Deleterious | 0.965 | Probably Damaging | 0.416 | Benign | 3.45 | Benign | 0.00 | Affected | 3.61 | 5 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||
c.407G>A | R136Q![]() | Benign | 1 | 6-33432704-G-A | 13 | 9.17e-6 | -11.146 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.190 | Likely Benign | -2.26 | Neutral | 0.957 | Probably Damaging | 0.342 | Benign | 3.52 | Benign | 0.01 | Affected | 3.61 | 5 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||
c.407G>C | R136P![]() | Likely Pathogenic | Uncertain | 1 | -11.952 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.277 | Likely Benign | -3.72 | Deleterious | 0.910 | Possibly Damaging | 0.578 | Possibly Damaging | 3.47 | Benign | 0.00 | Affected | 3.61 | 5 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||
c.416G>A | S139N![]() | Likely Benign | Uncertain | 1 | 6-33432713-G-A | 3 | 2.22e-6 | -4.584 | Likely Benign | 0.688 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -0.75 | Neutral | 0.149 | Benign | 0.047 | Benign | 4.14 | Benign | 0.24 | Tolerated | 3.61 | 5 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||
c.431C>T | T144M![]() | Likely Pathogenic | Uncertain | 2 | 6-33432728-C-T | 2 | 1.30e-6 | -11.228 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.118 | Likely Benign | -3.16 | Deleterious | 0.913 | Possibly Damaging | 0.333 | Benign | 3.73 | Benign | 0.00 | Affected | 3.61 | 5 | -1 | -1 | 2.6 | 30.09 | |||||||||||||||||||||||||||
c.43G>A | A15T![]() | Likely Benign | Uncertain | 1 | 6-33420307-G-A | 4 | 2.60e-6 | -3.720 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -0.08 | Neutral | 0.602 | Possibly Damaging | 0.017 | Benign | 4.16 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||
c.43G>C | A15P![]() | Likely Benign | Uncertain | 1 | -3.436 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -0.23 | Neutral | 0.880 | Possibly Damaging | 0.123 | Benign | 4.09 | Benign | 0.00 | Affected | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||
c.44C>T | A15V![]() | Likely Benign | Uncertain | 1 | 6-33420308-C-T | 1 | 6.49e-7 | -3.560 | Likely Benign | 0.161 | Likely Benign | Likely Benign | 0.105 | Likely Benign | 0.20 | Neutral | 0.602 | Possibly Damaging | 0.015 | Benign | 4.19 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||
c.451G>C | D151H![]() | Likely Pathogenic | Uncertain | 1 | 6-33432748-G-C | 2 | 1.26e-6 | -11.747 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.335 | Likely Benign | -3.90 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 3.86 | Benign | 0.00 | Affected | 3.61 | 5 | -1 | 1 | 0.3 | 22.05 | |||||||||||||||||||||||||||
c.453C>A | D151E![]() | Likely Benign | Uncertain | 1 | -5.662 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | -2.02 | Neutral | 0.984 | Probably Damaging | 0.967 | Probably Damaging | 3.99 | Benign | 0.11 | Tolerated | 3.61 | 5 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
c.455G>A | R152Q![]() | Uncertain | 1 | 6-33432752-G-A | 5 | 3.14e-6 | -10.336 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.181 | Likely Benign | -2.34 | Neutral | 0.997 | Probably Damaging | 0.968 | Probably Damaging | 3.89 | Benign | 0.00 | Affected | 3.61 | 5 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||
c.458C>A | T153N![]() | Likely Benign | Conflicting | 3 | -0.739 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.161 | Likely Benign | 0.88 | Neutral | 0.888 | Possibly Damaging | 0.537 | Possibly Damaging | 4.23 | Benign | 0.81 | Tolerated | 3.61 | 5 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||
c.467T>G | F156C![]() | Likely Pathogenic | Uncertain | 1 | -13.658 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.297 | Likely Benign | -3.54 | Deleterious | 0.999 | Probably Damaging | 0.990 | Probably Damaging | 3.92 | Benign | 0.00 | Affected | -4 | -2 | -0.3 | -44.04 | ||||||||||||||||||||||||||||||||
c.470G>A | R157H![]() | Uncertain | 1 | 6-33432767-G-A | 1 | 6.20e-7 | -10.235 | Likely Pathogenic | 0.604 | Likely Pathogenic | Likely Benign | 0.254 | Likely Benign | -2.23 | Neutral | 0.999 | Probably Damaging | 0.987 | Probably Damaging | 3.80 | Benign | 0.00 | Affected | 3.74 | 4 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||
c.484C>G | R162G![]() | Likely Benign | Uncertain | 1 | -6.985 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.190 | Likely Benign | -0.73 | Neutral | 0.487 | Possibly Damaging | 0.272 | Benign | 4.09 | Benign | 0.78 | Tolerated | 3.74 | 4 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||
c.484C>T | R162C![]() | Pathogenic | 2 | -8.157 | Likely Pathogenic | 0.787 | Likely Pathogenic | Ambiguous | 0.150 | Likely Benign | -2.05 | Neutral | 0.988 | Probably Damaging | 0.513 | Possibly Damaging | 4.00 | Benign | 0.11 | Tolerated | 3.74 | 4 | -4 | -3 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||
c.485G>A | R162H![]() | Uncertain | 1 | 6-33432782-G-A | 2 | 1.24e-6 | -9.730 | Likely Pathogenic | 0.480 | Ambiguous | Likely Benign | 0.167 | Likely Benign | -1.13 | Neutral | 0.957 | Probably Damaging | 0.513 | Possibly Damaging | 4.03 | Benign | 0.12 | Tolerated | 3.74 | 4 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||
c.48G>A | M16I![]() | Likely Benign | Uncertain | 1 | 6-33420312-G-A | 1 | 6.49e-7 | -2.198 | Likely Benign | 0.722 | Likely Pathogenic | Likely Benign | 0.057 | Likely Benign | -0.15 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.28 | Benign | 0.00 | Affected | 4.32 | 1 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||
c.491G>A | R164Q![]() | Uncertain | 1 | 6-33432788-G-A | 2 | 1.24e-6 | -11.208 | Likely Pathogenic | 0.600 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | -1.86 | Neutral | 0.957 | Probably Damaging | 0.342 | Benign | 3.82 | Benign | 0.00 | Affected | 3.74 | 4 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||
c.502C>T | H168Y![]() | Likely Benign | Benign | 1 | -8.914 | Likely Pathogenic | 0.264 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -1.53 | Neutral | 0.192 | Benign | 0.062 | Benign | 4.18 | Benign | 0.01 | Affected | 4.32 | 3 | 0 | 2 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||
c.505G>A | D169N![]() | Uncertain | 1 | -10.713 | Likely Pathogenic | 0.761 | Likely Pathogenic | Likely Benign | 0.110 | Likely Benign | -2.04 | Neutral | 0.079 | Benign | 0.052 | Benign | 4.07 | Benign | 0.01 | Affected | 3.74 | 4 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||
c.508C>T | R170W![]() | Likely Pathogenic | Uncertain | 2 | -11.660 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.241 | Likely Benign | -4.28 | Deleterious | 0.999 | Probably Damaging | 0.849 | Possibly Damaging | 3.84 | Benign | 0.00 | Affected | 3.74 | 4 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||
c.509G>A | R170Q![]() | Pathogenic/Likely path. | 5 | -9.021 | Likely Pathogenic | 0.798 | Likely Pathogenic | Ambiguous | 0.221 | Likely Benign | -2.31 | Neutral | 0.947 | Possibly Damaging | 0.342 | Benign | 3.91 | Benign | 0.00 | Affected | 3.74 | 4 | 1 | 1 | 1.0 | -28.06 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||
c.50C>T | S17F![]() | Likely Benign | Uncertain | 1 | 6-33420314-C-T | 10 | 6.49e-6 | -3.888 | Likely Benign | 0.637 | Likely Pathogenic | Likely Benign | 0.048 | Likely Benign | -0.99 | Neutral | 0.486 | Possibly Damaging | 0.032 | Benign | 3.99 | Benign | 0.00 | Affected | 4.32 | 1 | -2 | -3 | 3.6 | 60.10 | |||||||||||||||||||||||||||
c.514C>T | R172W![]() | Likely Pathogenic | Uncertain | 2 | 6-33435156-C-T | 9 | 5.58e-6 | -10.258 | Likely Pathogenic | 0.878 | Likely Pathogenic | Ambiguous | 0.228 | Likely Benign | -3.61 | Deleterious | 0.997 | Probably Damaging | 0.803 | Possibly Damaging | 3.95 | Benign | 0.00 | Affected | 3.61 | 5 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||
c.515G>A | R172Q![]() | Uncertain | 1 | 6-33435157-G-A | 3 | 1.86e-6 | -7.245 | In-Between | 0.465 | Ambiguous | Likely Benign | 0.135 | Likely Benign | -1.72 | Neutral | 0.804 | Possibly Damaging | 0.091 | Benign | 4.04 | Benign | 0.04 | Affected | 3.61 | 5 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||
c.526A>C | S176R![]() | Likely Benign | Uncertain | 1 | -6.492 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.247 | Likely Benign | 0.94 | Neutral | 0.718 | Possibly Damaging | 0.168 | Benign | 4.16 | Benign | 0.87 | Tolerated | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||
c.526A>G | S176G![]() | Uncertain | 1 | 6-33435168-A-G | 1 | 6.20e-7 | -7.541 | In-Between | 0.360 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -1.08 | Neutral | 0.131 | Benign | 0.039 | Benign | 4.08 | Benign | 0.22 | Tolerated | 3.54 | 6 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||
c.53A>G | Y18C![]() | Likely Benign | Uncertain | 1 | 6-33420317-A-G | 44 | 2.88e-5 | -2.658 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -0.56 | Neutral | 0.872 | Possibly Damaging | 0.206 | Benign | 4.04 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||
c.558G>C | L186F![]() | Likely Pathogenic | Uncertain | 1 | -11.861 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.132 | Likely Benign | -3.03 | Deleterious | 0.009 | Benign | 0.012 | Benign | 3.50 | Benign | 0.00 | Affected | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||
c.583G>C | A195P![]() | Likely Pathogenic | Likely Pathogenic | 1 | -9.715 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.152 | Likely Benign | -3.03 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.00 | Benign | 0.04 | Affected | 3.54 | 6 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||
c.59C>G | P20R![]() | Likely Benign | Uncertain | 1 | -3.548 | Likely Benign | 0.434 | Ambiguous | Likely Benign | 0.146 | Likely Benign | -0.15 | Neutral | 0.972 | Probably Damaging | 0.804 | Possibly Damaging | 4.33 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||
c.59C>T | P20L![]() | Likely Benign | Uncertain | 3 | -3.289 | Likely Benign | 0.464 | Ambiguous | Likely Benign | 0.100 | Likely Benign | -0.44 | Neutral | 0.909 | Possibly Damaging | 0.713 | Possibly Damaging | 4.27 | Benign | 0.00 | Affected | 4.32 | 1 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||
c.5G>A | S2N![]() | Likely Benign | Uncertain | 2 | 6-33420269-G-A | 3 | 1.96e-6 | -4.104 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -0.36 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.06 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||
c.68A>G | D23G![]() | Likely Benign | Uncertain | 1 | -2.622 | Likely Benign | 0.684 | Likely Pathogenic | Likely Benign | 0.100 | Likely Benign | -2.45 | Neutral | 0.805 | Possibly Damaging | 0.539 | Possibly Damaging | 3.50 | Benign | 0.00 | Affected | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||
c.70G>A | V24I![]() | Likely Benign | Uncertain | 1 | 6-33423479-G-A | 9 | 5.58e-6 | -3.701 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.25 | Neutral | 0.043 | Benign | 0.031 | Benign | 3.96 | Benign | 0.00 | Affected | 4.32 | 1 | 3 | 4 | 0.3 | 14.03 | |||||||||||||||||||||||||||
c.718G>A | D240N![]() | Likely Pathogenic | PH | Uncertain | 1 | -12.942 | Likely Pathogenic | 0.755 | Likely Pathogenic | Likely Benign | 0.701 | Likely Pathogenic | 0.22 | Likely Benign | 0.9 | 0.47 | Likely Benign | 0.35 | Likely Benign | 0.37 | Likely Benign | -4.37 | Deleterious | 0.993 | Probably Damaging | 0.984 | Probably Damaging | 5.88 | Benign | 0.01 | Affected | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||
c.719A>G | D240G![]() | Likely Pathogenic | PH | Uncertain | 1 | -12.825 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.912 | Likely Pathogenic | 1.85 | Ambiguous | 0.1 | 2.72 | Destabilizing | 2.29 | Destabilizing | 0.24 | Likely Benign | -6.19 | Deleterious | 0.993 | Probably Damaging | 0.984 | Probably Damaging | 5.79 | Benign | 0.01 | Affected | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||
c.73C>T | R25W![]() | Likely Benign | Uncertain | 2 | 6-33423482-C-T | 6 | 3.72e-6 | -5.133 | Likely Benign | 0.549 | Ambiguous | Likely Benign | 0.158 | Likely Benign | -1.60 | Neutral | 0.994 | Probably Damaging | 0.919 | Probably Damaging | 3.92 | Benign | 0.00 | Affected | 4.32 | 1 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||
c.74G>A | R25Q![]() | Likely Benign | Uncertain | 1 | 6-33423483-G-A | 15 | 9.29e-6 | -4.126 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -0.70 | Neutral | 0.829 | Possibly Damaging | 0.614 | Possibly Damaging | 4.01 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
c.767A>G | N256S (3D Viewer) ![]() | Likely Pathogenic | C2 | Likely Pathogenic | 1 | -10.640 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.707 | Likely Pathogenic | 0.31 | Likely Benign | 0.2 | 0.36 | Likely Benign | 0.34 | Likely Benign | 0.48 | Likely Benign | -4.33 | Deleterious | 0.997 | Probably Damaging | 0.970 | Probably Damaging | 5.87 | Benign | 0.02 | Affected | 3.39 | 15 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||
c.76G>A | G26R![]() | Likely Benign | Benign | 1 | 6-33423485-G-A | 3 | 1.86e-6 | -2.946 | Likely Benign | 0.678 | Likely Pathogenic | Likely Benign | 0.189 | Likely Benign | -2.22 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 3.87 | Benign | 0.00 | Affected | 4.32 | 1 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||
c.772C>T | R258C (3D Viewer) ![]() | Likely Pathogenic | C2 | Uncertain | 1 | 6-33437677-C-T | 1 | 6.20e-7 | -10.285 | Likely Pathogenic | 0.790 | Likely Pathogenic | Ambiguous | 0.771 | Likely Pathogenic | 1.17 | Ambiguous | 0.4 | 1.76 | Ambiguous | 1.47 | Ambiguous | 0.87 | Ambiguous | -6.79 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 5.77 | Benign | 0.00 | Affected | 3.39 | 15 | -3 | -4 | 7.0 | -53.05 | |||||||||||||||||
c.82T>C | S28P![]() | Likely Benign | Uncertain | 1 | -3.309 | Likely Benign | 0.051 | Likely Benign | Likely Benign | 0.047 | Likely Benign | 1.37 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.53 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
c.851T>C | L284P![]() | Likely Pathogenic | C2 | Likely Pathogenic | 1 | -15.588 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.794 | Likely Pathogenic | 5.83 | Destabilizing | 0.2 | 5.81 | Destabilizing | 5.82 | Destabilizing | 1.89 | Destabilizing | -6.17 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.64 | Pathogenic | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||
c.860A>C | D287A (3D Viewer) ![]() | Likely Pathogenic | C2 | Uncertain | 1 | -14.686 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.484 | Likely Benign | 0.30 | Likely Benign | 0.1 | -0.04 | Likely Benign | 0.13 | Likely Benign | 0.40 | Likely Benign | -7.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.58 | Pathogenic | 0.01 | Affected | 3.38 | 23 | -2 | 0 | 5.3 | -44.01 | ||||||||||||||||||||
c.862G>A | D288N (3D Viewer) ![]() | Likely Pathogenic | C2 | Uncertain | 1 | 6-33437767-G-A | 2 | 1.24e-6 | -10.535 | Likely Pathogenic | 0.521 | Ambiguous | Likely Benign | 0.321 | Likely Benign | -0.39 | Likely Benign | 0.1 | 0.01 | Likely Benign | -0.19 | Likely Benign | -0.03 | Likely Benign | -3.73 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.78 | Pathogenic | 0.05 | Affected | 3.38 | 23 | 1 | 2 | 0.0 | -0.98 | |||||||||||||||||
c.866T>C | M289T![]() | Likely Benign | C2 | Uncertain | 1 | -4.668 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.222 | Likely Benign | 0.73 | Ambiguous | 0.1 | 0.17 | Likely Benign | 0.45 | Likely Benign | -0.01 | Likely Benign | -0.47 | Neutral | 0.801 | Possibly Damaging | 0.315 | Benign | 1.83 | Pathogenic | 0.57 | Tolerated | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||
c.86T>C | M29T![]() | Likely Benign | Uncertain | 1 | -2.167 | Likely Benign | 0.122 | Likely Benign | Likely Benign | 0.199 | Likely Benign | -0.37 | Neutral | 0.018 | Benign | 0.184 | Benign | 4.33 | Benign | 0.00 | Affected | 4.32 | 1 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||
c.88C>T | H30Y![]() | Likely Benign | Uncertain | 1 | -3.047 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -1.84 | Neutral | 0.273 | Benign | 0.478 | Possibly Damaging | 3.99 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | 2 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||
c.892C>T | P298S (3D Viewer) ![]() | Likely Benign | C2 | Benign | 1 | 6-33437797-C-T | 5 | 3.10e-6 | -6.342 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.189 | Likely Benign | 1.38 | Ambiguous | 0.2 | 1.41 | Ambiguous | 1.40 | Ambiguous | 0.58 | Ambiguous | -1.20 | Neutral | 0.991 | Probably Damaging | 0.898 | Possibly Damaging | 2.03 | Pathogenic | 0.85 | Tolerated | 3.39 | 20 | -1 | 1 | 0.8 | -10.04 | |||||||||||||||||
c.910G>A | D304N (3D Viewer) ![]() | C2 | Uncertain | 1 | -6.194 | Likely Benign | 0.391 | Ambiguous | Likely Benign | 0.345 | Likely Benign | 0.30 | Likely Benign | 0.1 | -0.08 | Likely Benign | 0.11 | Likely Benign | 0.21 | Likely Benign | -4.18 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.81 | Pathogenic | 0.03 | Affected | 3.38 | 23 | 1 | 2 | 0.0 | -0.98 | |||||||||||||||||||||
c.929A>G | E310G (3D Viewer) ![]() | Likely Pathogenic | C2 | Pathogenic | 1 | -14.132 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.848 | Likely Pathogenic | 2.38 | Destabilizing | 0.7 | 3.56 | Destabilizing | 2.97 | Destabilizing | 0.36 | Likely Benign | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.12 | Pathogenic | 0.00 | Affected | 3.38 | 19 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||||
c.92G>A | R31Q![]() | Likely Benign | Uncertain | 1 | 6-33423501-G-A | 7 | 4.34e-6 | -4.434 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.92 | Neutral | 0.829 | Possibly Damaging | 0.614 | Possibly Damaging | 4.01 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
c.937G>A | E313K (3D Viewer) ![]() | Likely Pathogenic | C2 | Likely Benign | 1 | -12.902 | Likely Pathogenic | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.575 | Likely Pathogenic | 0.64 | Ambiguous | 0.6 | 1.40 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | -3.31 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 1.90 | Pathogenic | 0.02 | Affected | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||
c.958G>A | V320I (3D Viewer) ![]() | Likely Benign | C2 | Uncertain | 1 | -5.220 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.027 | Likely Benign | -0.27 | Likely Benign | 0.2 | 0.66 | Ambiguous | 0.20 | Likely Benign | 0.01 | Likely Benign | -0.21 | Neutral | 0.198 | Benign | 0.114 | Benign | 1.77 | Pathogenic | 0.45 | Tolerated | 3.38 | 23 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||||
c.961C>T | R321C (3D Viewer) ![]() | Likely Pathogenic | C2 | Conflicting | 2 | 6-33437866-C-T | 9 | 5.58e-6 | -10.025 | Likely Pathogenic | 0.387 | Ambiguous | Likely Benign | 0.495 | Likely Benign | 0.57 | Ambiguous | 0.1 | 0.56 | Ambiguous | 0.57 | Ambiguous | 0.18 | Likely Benign | -4.59 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.89 | Pathogenic | 0.01 | Affected | 3.38 | 23 | -3 | -4 | 7.0 | -53.05 | |||||||||||||||||
c.971G>A | R324Q (3D Viewer) ![]() | Likely Benign | C2 | Uncertain | 3 | 6-33437876-G-A | 3 | 1.86e-6 | -5.001 | Likely Benign | 0.173 | Likely Benign | Likely Benign | 0.307 | Likely Benign | 0.56 | Ambiguous | 0.1 | 0.63 | Ambiguous | 0.60 | Ambiguous | 1.02 | Destabilizing | -1.17 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.92 | Pathogenic | 0.41 | Tolerated | 3.39 | 22 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||
c.1480A>G | I494V (3D Viewer) ![]() | GAP | Conflicting | 2 | 6-33438512-A-G | 36 | 2.23e-5 | -7.102 | In-Between | 0.112 | Likely Benign | Likely Benign | 0.439 | Likely Benign | 1.16 | Ambiguous | 0.0 | 0.71 | Ambiguous | 0.94 | Ambiguous | 1.02 | Destabilizing | -0.83 | Neutral | 0.278 | Benign | 0.179 | Benign | -1.30 | Pathogenic | 0.07 | Tolerated | 3.37 | 35 | 4 | 3 | -0.3 | -14.03 | 248.6 | 29.3 | 0.0 | 0.0 | -1.1 | 0.5 | X | Potentially Benign | The sec-butyl side chain of Ile494, located in an α-helix (res. Leu489-Glu519), packs against hydrophobic residues (e.g., Phe484, Leu465, Trp572, Ala493, Met468) in an inter-helix space (res. Leu489-Glu519 and res. Ala461-Phe476). In the variant simulations, the hydrophobic iso-propyl side chain of Val494, which is of a similar size and has similar physicochemical properties to Ile494 in the WT, resides similarly in the inter-helix hydrophobic space. Thus, no negative effects on the protein structure are observed. | |||||||||
c.2162T>G | I721S (3D Viewer) ![]() | Likely Pathogenic | GAP | Uncertain | 1 | -14.032 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.466 | Likely Benign | 3.91 | Destabilizing | 0.1 | 3.96 | Destabilizing | 3.94 | Destabilizing | 2.28 | Destabilizing | -5.26 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.21 | Pathogenic | 0.00 | Affected | 3.50 | 9 | -1 | -2 | -5.3 | -26.08 | 203.3 | 49.3 | -0.1 | 0.0 | -1.1 | 0.0 | X | Uncertain | The sec-butyl side chain of Ile721, located on an α-helix (res. Leu714-Arg726), engages in hydrophobic packing with other residues in the hydrophobic inter-helix space, such as Phe420, Tyr417, His693, and Leu717. In the variant simulations, the hydroxyl side chain of Ser721 forms hydrogen bonds with nearby residues, such as Leu717 and His693. Although no major structural changes are observed during the variant simulations, the hydrophilic residue Ser721 could disrupt the hydrophobic packing during folding. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | |||||||||||
c.1706T>C | F569S (3D Viewer) ![]() | Likely Pathogenic | GAP | Likely Pathogenic | 2 | -13.384 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.916 | Likely Pathogenic | 5.70 | Destabilizing | 0.1 | 5.38 | Destabilizing | 5.54 | Destabilizing | 2.45 | Destabilizing | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.32 | Pathogenic | 0.00 | Affected | 3.37 | 34 | -3 | -2 | -3.6 | -60.10 | 213.7 | 67.9 | -0.1 | 0.0 | -1.0 | 0.1 | X | Potentially Pathogenic | Phe569 is located on an α-helix (res. Arg563-Glu578). In the WT simulations, the phenyl side chain of Phe569 packs with hydrophobic residues such as Trp572, Leu565, Ile589, Ile667, and Phe561, originating from three different α-helices (res. Ala533-Val560, res. Arg563-Glu578, and res. Ser641-Glu666). In the variant simulations, the acceptor/donor hydroxyl group of Ser569 forms hydrogen bonds with the carbonyl groups of Glu567 and Lys566 on the same α-helix, which could affect the α-helix integrity, although this is not observed in the simulations. While the simulations do not show large-scale effects, the residue swap could have a substantial impact on the protein structure due to the fundamental role of hydrophobic packing during protein folding. | |||||||||||
c.1714T>G | W572G (3D Viewer) ![]() | Likely Pathogenic | GAP | Uncertain | 1 | -17.692 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.900 | Likely Pathogenic | 6.57 | Destabilizing | 0.2 | 7.57 | Destabilizing | 7.07 | Destabilizing | 1.83 | Destabilizing | -11.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.24 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -7 | -2 | 0.5 | -129.16 | 195.2 | 127.9 | 0.0 | 0.0 | -1.0 | 0.0 | X | Potentially Pathogenic | The introduced residue Gly572, located in an α-helix (res. Arg563-Glu578), is considerably smaller than the tryptophan it replaced. The indole ring of the Trp572 side chain lies in a hydrophobic inter-helix space, where it makes extensive hydrophobic interactions with nearby residues such as Met470, Phe569, Leu588, and Ile589. In the variant simulations, all these favorable packing interactions are completely removed, as the introduced residue Gly572 essentially lacks a side chain altogether. Although not observed in the simulations, the residue swap could also weaken the integrity of the helix (res. Arg563-Glu578), as glycine is known as an “α-helix breaker.” Overall, the residue swap is highly likely to cause critical protein folding problems that are underestimated based on the effects seen in the variant simulations. | |||||||||||
c.1390T>G | F464V (3D Viewer) ![]() | Likely Pathogenic | GAP | Uncertain | 1 | -12.254 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.592 | Likely Pathogenic | 3.61 | Destabilizing | 0.1 | 2.89 | Destabilizing | 3.25 | Destabilizing | 1.40 | Destabilizing | -6.96 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 3.36 | Benign | 0.04 | Affected | 3.37 | 34 | -1 | -1 | 1.4 | -48.04 | 210.1 | 40.5 | -0.1 | 0.0 | -0.9 | 0.3 | X | Potentially Pathogenic | The phenyl ring of Phe464, located in the middle of an α helix (res. Ala461–Phe476), packs against hydrophobic residues (e.g., Met468, Leu451, Leu455, and Tyr428) in the inter-helix space formed with two other α helices (res. Asn440-Lys460 and res. Pro413-Glu436). The iso-propyl side chain of Val464 is similarly hydrophobic but considerably smaller than the original phenyl ring of Phe464. To compensate for the size difference, neighboring residues need to fill in the gap in the variant simulations.The phenolic side chain of Tyr428, located at the middle bend of an α helix (res. Glu436-Pro413), assumes a new position in the inter-helix space or rotates inward next to the third α helix (res. Asn440-Lys460) when the stable H-bond between Tyr428 and Asp467 seen in the WT simulations breaks. The residue swap also leads to the loss of the methionine-aromatic interaction between the Met468 and Phe464 side chains, which could weaken the integrity of the parent α helix (res. Ala461-Phe476). Although the simulations likely underestimate the full adverse effect of the introduced mutation during folding, the two opposing α helices (res. Ala461–Phe476 and res. Glu436-Pro413) move substantially closer to each other in the variant simulations. | |||||||||||
c.1408A>C | M470L (3D Viewer) ![]() | Likely Pathogenic | GAP | Likely Benign | 1 | 6-33438440-A-C | 1 | 6.20e-7 | -8.993 | Likely Pathogenic | 0.406 | Ambiguous | Likely Benign | 0.678 | Likely Pathogenic | 0.73 | Ambiguous | 0.1 | 0.84 | Ambiguous | 0.79 | Ambiguous | 1.04 | Destabilizing | -2.72 | Deleterious | 0.484 | Possibly Damaging | 0.654 | Possibly Damaging | -1.22 | Pathogenic | 0.16 | Tolerated | 3.37 | 34 | 4 | 2 | 1.9 | -18.03 | 225.3 | 17.9 | 0.0 | 0.0 | -0.8 | 0.5 | X | Potentially Benign | The thioether group of Met470, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues in the inter-helix space (e.g., Val473, Leu558) formed by two other α helices (res. Ser604–Arg581, res. Pro562–Arg579). In the WT simulations, Met470 also packs against the positively charged guanidinium groups of Arg575, Arg429, and Arg579, which form salt bridges with the negatively charged carboxylate groups of the Asp474 and Asp467 side chains at the protein surface. In the variant simulations, the iso-butyl side chain of Leu470 packs similarly with the hydrophobic residues as methionine, resulting in no negative effects on the protein structure during the simulation. | ||||||||
c.1424G>A | R475Q (3D Viewer) ![]() | Likely Pathogenic | GAP | Uncertain | 2 | 6-33438456-G-A | 5 | 3.10e-6 | -12.087 | Likely Pathogenic | 0.721 | Likely Pathogenic | Likely Benign | 0.632 | Likely Pathogenic | 0.71 | Ambiguous | 0.1 | 0.12 | Likely Benign | 0.42 | Likely Benign | 0.82 | Ambiguous | -3.65 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.39 | 28 | 1 | 1 | 1.0 | -28.06 | 253.6 | 52.7 | 0.0 | 0.0 | -0.8 | 0.0 | X | X | X | Potentially Pathogenic | In the WT simulations, the guanidinium group of Arg475, located near the end of an α-helix (res. Ala461-Phe476), stacks with the phenyl ring of Phe476 and forms a salt bridge with Glu472. Additionally, Arg475 occasionally forms another salt bridge with the carboxylate group of Glu486 on the α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. Therefore, Arg475 potentially plays a key role in positioning the loop by interacting with Glu486, which is necessary for the positioning of the “arginine finger” (Arg485) and, ultimately, for RasGTPase activation. In the variant simulations, Asn475 forms a hydrogen bond with Arg479 on the proceeding α-α loop. The absence of Phe476/Arg475 stacking and the Arg475-Glu472 salt bridge weakens the integrity of the terminal end of the α-helix during the variant simulations. Lastly, the potential effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||
c.2143C>T | P715S (3D Viewer) ![]() | GAP | Likely Pathogenic | 1 | 6-33441608-C-T | 1 | 6.20e-7 | -7.635 | In-Between | 0.787 | Likely Pathogenic | Ambiguous | 0.277 | Likely Benign | 3.54 | Destabilizing | 0.0 | 0.81 | Ambiguous | 2.18 | Destabilizing | 0.94 | Ambiguous | -7.17 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.43 | Benign | 0.01 | Affected | 3.50 | 9 | 1 | -1 | 0.8 | -10.04 | 231.8 | -14.0 | -0.1 | 0.0 | -0.8 | 0.1 | X | Uncertain | Pro715, along with Gly712 and Pro713, are located in a hinge region of an α-helix making a ~90-degree turn (res. Lys705-Leu725). In the WT simulations, the pyrrolidine side chain of Pro715, lacking the backbone amide groups altogether, forces the tight helix turn to take place while also hydrophobically packing with nearby residues (e.g., Leu700, Leu708, Leu714, and Leu718). Leu715, with a normal amide backbone, could potentially affect protein folding and turn formation, although this was not observed in the variant simulations. Additionally, the hydroxyl group of the Ser715 side chain can form hydrogen bonds with the backbone carbonyl group of Gly712 and disrupt the hydrophobic packing arrangement of the leucine residues from the neighboring α-helices, impacting the GAP domain tertiary assembly. | |||||||||
c.1214G>A | R405H (3D Viewer) ![]() | Likely Pathogenic | C2 | Conflicting | 2 | 6-33438119-G-A | 4 | 2.48e-6 | -9.081 | Likely Pathogenic | 0.706 | Likely Pathogenic | Likely Benign | 0.371 | Likely Benign | 2.79 | Destabilizing | 0.6 | 1.85 | Ambiguous | 2.32 | Destabilizing | 1.26 | Destabilizing | -4.54 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.65 | Benign | 0.01 | Affected | 3.38 | 28 | 2 | 0 | 1.3 | -19.05 | 214.0 | 102.2 | -0.1 | 0.0 | -0.7 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg405, located in an anti-parallel β sheet strand of the C2 domain (res. Pro398-Ile411), forms a salt bridge with the carboxylate group of the Glu446 side chain from an opposing α helix (res. Val441-Ser457) in the GAP domain. The positively charged Arg405 side chain also stacks with the aromatic ring of the Phe358 side chain from a loop preceding the β strand (res. Thr359-Thr366), which could assist in maintaining the anti-parallel strand arrangement.In the variant simulations, the imidazole ring of His405 does not stack with the aromatic ring of Phe358 nor form any lasting H-bonds with the loop residues. The imidazole ring of His405 (neutral and epsilon protonated in the simulations) is unable to form a salt bridge with Glu446, which could affect the tertiary structure assembly, although this is not apparent based on the variant simulations. | ||||||||
c.1610C>T | A537V (3D Viewer) ![]() | Likely Benign | GAP | Likely Benign | 1 | 6-33438853-C-T | 7 | 4.34e-6 | -6.888 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.382 | Likely Benign | 0.54 | Ambiguous | 0.0 | -0.05 | Likely Benign | 0.25 | Likely Benign | 0.41 | Likely Benign | -1.97 | Neutral | 0.977 | Probably Damaging | 0.469 | Possibly Damaging | -1.26 | Pathogenic | 0.24 | Tolerated | 3.37 | 35 | 0 | 0 | 2.4 | 28.05 | 220.3 | -45.1 | 0.0 | 0.0 | -0.7 | 0.1 | X | Potentially Benign | Ala537 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala537 is on the surface and does not form any interactions. In the variant simulations, the iso-propyl side chain of Val537 is also on the surface, similar to Ala537 in the WT, causing no negative structural effects. | ||||||||
c.1487A>G | E496G (3D Viewer) ![]() | Likely Pathogenic | GAP | Uncertain | 1 | -13.529 | Likely Pathogenic | 0.850 | Likely Pathogenic | Ambiguous | 0.825 | Likely Pathogenic | 1.83 | Ambiguous | 0.1 | 1.76 | Ambiguous | 1.80 | Ambiguous | 0.92 | Ambiguous | -6.16 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.45 | Pathogenic | 0.02 | Affected | 3.37 | 35 | 0 | -2 | 3.1 | -72.06 | 173.9 | 103.1 | 0.0 | 0.0 | -0.7 | 0.0 | X | X | Potentially Pathogenic | Glu496 is located in the α-helix (res. Leu489-Glu519), and its carboxylate group forms salt bridges with the neighbouring residues Lys492 and Arg499 in the WT simulations. Glu496 also forms a hydrogen bond with Ser449 on an opposing helix (res. Val441-Ser457). In the variant simulations, Gly496 cannot form these salt bridges, which could weaken the secondary structure. Additionally, the loss of the hydrogen bond with Ser449 on the opposite helix can weaken the tertiary structure assembly. Moreover, glycine is an α-helix breaker, and it is seen to weaken the integrity of the helix as the hydrogen bonding between the backbone atoms of Gly496 and Ala493 breaks down. Also, due to its location at the GAP-Ras interface, the interaction of Glu496 with Arg499 and Lys492 might play a role in complex association and stability, which cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||
c.1718G>T | R573L (3D Viewer) ![]() | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -13.120 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.833 | Likely Pathogenic | 1.30 | Ambiguous | 0.6 | 1.11 | Ambiguous | 1.21 | Ambiguous | 0.80 | Ambiguous | -5.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.41 | Pathogenic | 0.01 | Affected | 3.37 | 35 | -3 | -2 | 8.3 | -43.03 | 237.4 | 60.7 | 0.0 | 0.0 | -0.7 | 0.3 | X | X | Potentially Pathogenic | The guanidinium group of Arg573, located in an α-helix (res. Arg563-Glu578), forms a salt bridge with the carboxylate groups of Glu582 and/or Asp586 from a nearby α-helix (res. Glu582-Met603) in the WT simulations. Additionally, the Arg573 side chain stacks planarly with the aromatic phenol ring of Tyr665 and hydrogen bonds with the hydroxyl group of Ser668 from another α-helix (res. Ser641-Ser668). In the variant simulations, the aliphatic iso-butyl group of the Leu573 side chain fails to establish any of these interactions, which, in turn, lowers the integrity of the opposing α-helix end (res. Glu582-Met603). Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process. | 10.1016/j.ajhg.2020.11.011 | |||||||||
c.1997A>G | E666G (3D Viewer) ![]() | Likely Pathogenic | GAP | Likely Benign | 1 | 6-33441256-A-G | 10 | 6.20e-6 | -12.261 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.522 | Likely Pathogenic | 1.57 | Ambiguous | 0.1 | 1.46 | Ambiguous | 1.52 | Ambiguous | 0.93 | Ambiguous | -6.25 | Deleterious | 1.000 | Probably Damaging | 0.970 | Probably Damaging | 3.37 | Benign | 0.02 | Affected | 3.38 | 28 | 0 | -2 | 3.1 | -72.06 | 173.9 | 98.5 | 0.0 | 0.0 | -0.7 | 0.0 | X | Potentially Pathogenic | In the WT simulations, the carboxylate group of Glu666, located on the α-helix (res. Ser641-Glu666), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), such as Lys566, Thr672, and Asn669. In the variant simulations, the carbonyl group of Gly666 occasionally forms hydrogen bonds with Lys566 and Asn669. However, Gly666 lacks a side chain and thus cannot maintain as well-coordinated a hydrogen-bond network as Glu666 in the WT, which may affect the tertiary structure assembly. | ||||||||
c.2047A>G | I683V (3D Viewer) ![]() | Likely Benign | GAP | Uncertain | 1 | 6-33441306-A-G | 2 | 1.24e-6 | -7.588 | In-Between | 0.138 | Likely Benign | Likely Benign | 0.112 | Likely Benign | 0.90 | Ambiguous | 0.0 | 0.60 | Ambiguous | 0.75 | Ambiguous | 0.76 | Ambiguous | -0.78 | Neutral | 0.538 | Possibly Damaging | 0.080 | Benign | 3.35 | Benign | 0.14 | Tolerated | 3.42 | 17 | 4 | 3 | -0.3 | -14.03 | 215.6 | 29.1 | 0.0 | 0.0 | -0.7 | 0.1 | X | Potentially Benign | The sec-butyl side chain of Ile683, located in an entangled α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), is sterically packed against His453 and Glu688. In the variant simulations, the iso-propyl side chain of Val683 has similar size and physicochemical properties as Ile630 in the WT, and thus, it is able to maintain similar interactions in the inter-helix space. Consequently, no negative structural effects are observed during the simulations due to the residue swap. | ||||||||
c.2075T>C | L692P (3D Viewer) ![]() | Likely Pathogenic | GAP | Uncertain | 1 | -16.447 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.668 | Likely Pathogenic | 9.19 | Destabilizing | 0.1 | 13.20 | Destabilizing | 11.20 | Destabilizing | 1.69 | Destabilizing | -6.98 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.06 | Benign | 0.00 | Affected | 3.42 | 17 | -3 | -3 | -5.4 | -16.04 | 186.2 | 62.8 | -0.2 | 0.1 | -0.7 | 0.3 | X | Potentially Pathogenic | The isobutyl side chain of Leu692, located in the middle of an α-helix (res. Leu685-Gln702), engages in hydrophobic packing with nearby residues (e.g., Leu441, Leu431, Leu696) in the inter-helix space. Prolines lack a free amide group necessary for hydrogen bonding with the carbonyl group of Glu688 in the same manner as Leu692 in the WT. Consequently, the residue swap with proline disrupts the continuity of the secondary structure element in the variant simulations. Additionally, the side chain of Pro692 is not as optimal as Leu692 for hydrophobic packing in the inter-helix space. | |||||||||||
c.2089T>C | W697R (3D Viewer) ![]() | Likely Pathogenic | GAP | Likely Benign | 1 | 6-33441348-T-C | 1 | 6.20e-7 | -10.020 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.401 | Likely Benign | 1.14 | Ambiguous | 0.1 | 1.18 | Ambiguous | 1.16 | Ambiguous | 1.25 | Destabilizing | -9.50 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 3.45 | Benign | 0.02 | Affected | 3.46 | 13 | 2 | -3 | -3.6 | -30.03 | 254.4 | -41.2 | 0.0 | 0.0 | -0.7 | 0.0 | X | Potentially Benign | The indole ring of Trp697, located on the outer surface of an α-helix (res. Leu685-Val699), is not involved in any long-lasting interactions in the WT simulations. In the variant simulations, the positively charged guanidinium side chain of Arg697 occasionally forms hydrogen bonds with nearby residues, such as Ser722 and Asn719. However, similar to Trp697 in the WT, Arg697 does not form any long-lasting interactions and thus does not induce any negative structural effects in the simulations. | ||||||||
c.1084T>C | W362R (3D Viewer) ![]() | Likely Pathogenic | C2 | Pathogenic | 2 | -14.004 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.706 | Likely Pathogenic | 2.64 | Destabilizing | 0.3 | 3.90 | Destabilizing | 3.27 | Destabilizing | 1.10 | Destabilizing | -12.87 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 3.39 | 24 | 2 | -3 | -3.6 | -30.03 | 287.5 | -34.1 | -0.2 | 0.1 | -0.6 | 0.2 | X | X | X | Potentially Pathogenic | The indole ring of Trp362, located on the surface of an anti-parallel β sheet (res. Thr359-Pro364) in the C2 domain, stacks with nearby residues (e.g., Arg401, Arg272). In the variant simulations, the guanidinium group of the introduced residue Arg362 forms a salt bridge with the carboxylate group of Glu273 and, like Trp362, stacks with other arginine residues (e.g., Arg401, Arg272). This residue is at both the C2-membrane interface and the C2-RasGTPase interface, so the residue swap could potentially affect both interactions. However, these phenomena cannot be addressed using solvent-only simulations. Notably, Arg272, which stacks with both the non-mutated Trp362 and the mutated Arg362, forms a salt bridge directly with Asp105 of Ras in the WT simulations. Therefore, the residue swap could affect the C2 domain stability, the SynGAP-membrane association, and the SynGAP-Ras association. | 10.1016/j.ajhg.2020.11.011 | ||||||||
c.1118G>T | G373V (3D Viewer) ![]() | Likely Benign | C2 | Uncertain | 1 | 6-33438023-G-T | 6 | 5.03e-6 | -6.062 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.428 | Likely Benign | 5.32 | Destabilizing | 3.2 | 0.82 | Ambiguous | 3.07 | Destabilizing | 0.09 | Likely Benign | -0.98 | Neutral | 0.007 | Benign | 0.001 | Benign | 3.90 | Benign | 0.00 | Affected | 3.53 | 16 | -1 | -3 | 4.6 | 42.08 | 207.6 | -68.1 | 1.9 | 1.1 | -0.6 | 0.1 | Uncertain | Gly373 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Val373 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on the Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
c.1625A>G | N542S (3D Viewer) ![]() | Likely Pathogenic | GAP | Likely Benign | 1 | -9.675 | Likely Pathogenic | 0.767 | Likely Pathogenic | Likely Benign | 0.752 | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 0.99 | Ambiguous | 0.99 | Ambiguous | 0.91 | Ambiguous | -4.40 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | -1.36 | Pathogenic | 0.13 | Tolerated | 3.37 | 35 | 1 | 1 | 2.7 | -27.03 | 212.5 | 32.1 | 0.0 | 0.0 | -0.6 | 0.3 | X | Potentially Pathogenic | Asn542 is located in an α-helix (res. Ala533-Val560) next to an α-α loop between two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the carboxamide group of the Asn542 side chain forms a hydrogen bond with the backbone carbonyl group of Asn523 and packs favourably against Glu522 from the loop. In contrast, in the variant simulations, the hydroxyl group of the Ser542 side chain is unable to maintain either the hydrogen bond with Asn523 or the packing against the Glu522 side chain. Instead, the hydroxyl group of Ser542 occasionally forms a hydrogen bond with the backbone carbonyl group of Glu538.Altogether, the residue swap results in a looser helix-loop association, which is especially evident in the third replica simulation, where Asn523 moves away from its initial placement next to the α-helix. In short, based on the simulations, the residue swap weakens the GAP domain tertiary structure assembly, which in turn could negatively affect protein folding. | |||||||||||
c.1718G>A | R573Q (3D Viewer) ![]() | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -9.900 | Likely Pathogenic | 0.923 | Likely Pathogenic | Ambiguous | 0.733 | Likely Pathogenic | 2.28 | Destabilizing | 0.8 | 1.94 | Ambiguous | 2.11 | Destabilizing | 1.08 | Destabilizing | -3.16 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.31 | Pathogenic | 0.12 | Tolerated | 3.37 | 35 | 1 | 1 | 1.0 | -28.06 | 230.1 | 49.9 | 0.0 | 0.0 | -0.6 | 0.0 | X | X | Potentially Pathogenic | The guanidinium group of Arg573, located in an α-helix (res. Arg563-Glu578), forms a salt bridge with the carboxylate groups of Glu582 and/or Asp586 from a nearby α-helix (res. Glu582-Met603) in the WT simulations. Additionally, the Arg573 side chain stacks planarly with the aromatic phenol ring of Tyr665 and hydrogen bonds with the hydroxyl group of Ser668 from another α-helix (res. Ser641-Ser668). In the variant simulations, although the carboxamide group of the Gln573 side chain can hydrogen bond with the carboxylate group of Glu582 or the hydroxyl group of Ser668, these interactions are not as coordinated, stable, or strong as those of the positively charged Arg573. Consequently, the integrity of the opposing α-helix end (res. Glu582-Met603) is weakened. Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process. | ||||||||||
c.2071A>C | T691P (3D Viewer) ![]() | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -13.801 | Likely Pathogenic | 0.905 | Likely Pathogenic | Ambiguous | 0.214 | Likely Benign | 5.04 | Destabilizing | 0.4 | 6.09 | Destabilizing | 5.57 | Destabilizing | 1.27 | Destabilizing | -3.43 | Deleterious | 1.000 | Probably Damaging | 0.952 | Probably Damaging | 3.43 | Benign | 0.06 | Tolerated | 3.43 | 14 | 0 | -1 | -0.9 | -3.99 | 188.9 | 33.0 | 0.1 | 0.0 | -0.6 | 0.0 | X | X | Potentially Pathogenic | The hydroxyl side chain of Thr691, located in an α-helix (res. Leu696-Leu685), can form hydrogen bonds with the backbone carbonyl and the side chain guanidinium group of Arg687. This interaction facilitates the simultaneous formation of salt bridges between Arg687 and Glu688 on the same α-helix. Additionally, Thr691 occasionally interacts with the thioether side chain of Met409 in an anti-parallel β-sheet of the C2 domain (res. Ile411-Ala399), although this interaction is not consistently maintained throughout the WT simulations. In the variant simulations, the pyrrolidine side chain of Pro691 lacks hydrogen bond donors, making a similar setup impossible. Moreover, proline lacks a free amide group necessary for hydrogen bonding with the carbonyl group of Arg687, introducing a slight bend in the α-helix and compromising its integrity. | ||||||||||
c.2087T>C | L696P (3D Viewer) ![]() | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -16.926 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.678 | Likely Pathogenic | 6.66 | Destabilizing | 0.2 | 10.84 | Destabilizing | 8.75 | Destabilizing | 2.13 | Destabilizing | -6.58 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.00 | Benign | 0.00 | Affected | 3.46 | 13 | -3 | -3 | -5.4 | -16.04 | 180.6 | 65.9 | 0.1 | 0.0 | -0.6 | 0.1 | X | Potentially Pathogenic | The isobutyl side chain of Leu696, located in the middle of an α-helix (res. Leu685-Gln702), engages in hydrophobic packing with nearby residues (e.g., Leu441, Leu431, Leu692, Leu714) in the inter-helix space. Prolines lack a free amide group necessary for hydrogen bonding with the carbonyl group of Leu692 in the same manner as Leu696 in the WT. Consequently, the residue swap with proline disrupts the continuity of the secondary structure element in the variant simulations. Additionally, the side chain of Pro696 is not as optimal as Leu696 for hydrophobic packing in the inter-helix space. | |||||||||||
c.703T>C | S235P (3D Viewer) ![]() | Likely Pathogenic | PH | Likely Pathogenic | 1 | -14.857 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.870 | Likely Pathogenic | 4.02 | Destabilizing | 0.1 | 6.91 | Destabilizing | 5.47 | Destabilizing | 1.23 | Destabilizing | -4.24 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 5.47 | Benign | 0.01 | Affected | 3.40 | 14 | 1 | -1 | -0.8 | 10.04 | 201.5 | 17.0 | 0.1 | 0.0 | -0.6 | 0.0 | X | Potentially Pathogenic | In the WT, the hydroxyl group of Ser235, located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Phe231) and an α helix (residues Ala236-Val250), forms hydrogen bonds with the GAP domain loop residue Glu680 and with the backbone amide groups of Ala237 and Glu238 from the α helix. In the variant simulations, the pyrrolidine ring of Pro235 cannot stabilize the α helix end or maintain tertiary bonding interactions between the PH and GAP domains via hydrogen bonding as effectively as serine. | |||||||||||
c.1142G>T | G381V (3D Viewer) ![]() | Likely Benign | C2 | Uncertain | 1 | 6-33438047-G-T | 2 | 1.25e-6 | -5.967 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.618 | Likely Pathogenic | 7.16 | Destabilizing | 1.0 | 4.10 | Destabilizing | 5.63 | Destabilizing | -0.32 | Likely Benign | -0.95 | Neutral | 0.386 | Benign | 0.157 | Benign | 1.32 | Pathogenic | 0.10 | Tolerated | 4.32 | 9 | -1 | -3 | 4.6 | 42.08 | 214.6 | -68.8 | 0.3 | 0.7 | -0.5 | 0.3 | Uncertain | Gly381 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Val381 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effects on Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
c.1160G>T | G387V (3D Viewer) ![]() | Likely Benign | C2 | Uncertain | 1 | 6-33438065-G-T | 22 | 1.37e-5 | -6.199 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 0.390 | Likely Benign | 5.13 | Destabilizing | 1.8 | 6.44 | Destabilizing | 5.79 | Destabilizing | -0.33 | Likely Benign | -0.54 | Neutral | 0.069 | Benign | 0.077 | Benign | 1.32 | Pathogenic | 0.01 | Affected | 4.32 | 3 | -1 | -3 | 4.6 | 42.08 | 207.7 | -68.4 | -0.7 | 0.8 | -0.5 | 0.1 | Uncertain | Gly387 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. This loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play significant roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Val387 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. Since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
c.1172G>T | G391V (3D Viewer) ![]() | Likely Benign | C2 | Likely Benign | 1 | 6-33438077-G-T | 3 | 1.86e-6 | -6.642 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.595 | Likely Pathogenic | 4.23 | Destabilizing | 1.3 | 4.81 | Destabilizing | 4.52 | Destabilizing | -0.11 | Likely Benign | -0.98 | Neutral | 0.994 | Probably Damaging | 0.887 | Possibly Damaging | 1.32 | Pathogenic | 0.10 | Tolerated | 3.69 | 8 | -1 | -3 | 4.6 | 42.08 | 228.6 | -69.0 | 0.0 | 0.8 | -0.5 | 0.3 | Uncertain | Gly387 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. This loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play significant roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Val391 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. Since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
c.1667A>G | N556S (3D Viewer) ![]() | GAP | Uncertain | 1 | 6-33438910-A-G | 3 | 1.86e-6 | -6.576 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.449 | Likely Benign | 0.52 | Ambiguous | 0.1 | 0.14 | Likely Benign | 0.33 | Likely Benign | 0.16 | Likely Benign | -3.60 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | -1.22 | Pathogenic | 0.14 | Tolerated | 3.37 | 35 | 1 | 1 | 2.7 | -27.03 | 198.8 | 31.0 | 0.0 | 0.0 | -0.5 | 0.2 | X | Potentially Benign | Asn556 is located on the outer surface of an α-helix (res. Ala533-Val560). The carboxamide group of Asn556 forms hydrogen bonds with nearby residues such as Lys553 and Cys552. It also forms a hydrogen bond with the backbone carbonyl group of Cys552, which weakens the α-helix integrity. In the variant simulations, the hydroxyl group of Ser556 forms a more stable hydrogen bond with the backbone carbonyl oxygen of the same helix residue, Cys552, compared to Asn556 in the WT. Serine has a slightly lower propensity to reside in an α-helix than asparagine, which may exacerbate the negative effect on the α-helix integrity. However, the residue swap does not cause negative structural effects during the simulations. | |||||||||
c.1787G>T | R596L (3D Viewer) ![]() | Likely Pathogenic | GAP | Uncertain | 1 | -13.197 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.756 | Likely Pathogenic | 1.51 | Ambiguous | 0.3 | -0.58 | Ambiguous | 0.47 | Likely Benign | -0.02 | Likely Benign | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -3 | -2 | 8.3 | -43.03 | 234.2 | 63.4 | -0.1 | 0.0 | -0.5 | 0.6 | X | X | Potentially Pathogenic | The guanidinium group of Arg596, located in an α helix (res. Glu582-Met603), forms a salt bridge with the carboxylate group of Glu495 from another α helix (res. Leu489-Glu519). In the WT simulations, the side chain of Arg596 hydrogen bonds with the backbone carbonyl groups of Asn487, Glu486, Arg485, and Phe484. Additionally, Arg596 can hydrogen bond with the carboxamide group of the Asn487 side chain on an opposing loop that links two α helices (res. Ala461-Arg475, res. Leu489-Glu519).However, in the variant simulations, the branched hydrocarbon side chain of Leu596 cannot form any of the hydrogen bonds or salt bridges maintained by the considerably bulkier and positively charged Arg596 side chain. Instead, Leu596 packs hydrophobically with the phenyl ring of Phe484 in the linker loop or residues from the opposing helix (e.g., Ile494, Thr491).Thus, the residue swap could affect the tertiary structure assembly more profoundly than observed in the simulations. Notably, Arg596 plays a key role in positioning the aforementioned loop, which is crucial for the placement of the “arginine finger” or the Arg485 side chain during RasGTPase activation. | 10.1016/j.ajhg.2020.11.011 | |||||||||
c.2147G>A | R716Q (3D Viewer) ![]() | GAP | Conflicting | 2 | 6-33441612-G-A | 4 | 2.48e-6 | -8.338 | Likely Pathogenic | 0.308 | Likely Benign | Likely Benign | 0.210 | Likely Benign | -0.01 | Likely Benign | 0.0 | 0.47 | Likely Benign | 0.23 | Likely Benign | 0.58 | Ambiguous | -3.14 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 3.35 | Benign | 0.02 | Affected | 3.50 | 9 | 1 | 1 | 1.0 | -28.06 | 250.0 | 48.9 | 0.0 | 0.0 | -0.5 | 0.0 | X | Uncertain | The guanidinium group of Arg716, located on the outer surface of an α-helix (res. Leu714-Arg726), forms a salt bridge with the carboxylate group of Asp720. In the variant simulations, the carboxamide group of Gln716 also forms a hydrogen bond with the carboxylate group of Asp720, although this bond is weaker than the Arg716 salt bridge in the WT. Overall, no adverse effects on the protein structure are observed in the simulations. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | |||||||||
c.773G>A | R258H (3D Viewer) ![]() | C2 | Benign/Likely benign | 3 | 6-33437678-G-A | 10 | 6.20e-6 | -10.533 | Likely Pathogenic | 0.525 | Ambiguous | Likely Benign | 0.830 | Likely Pathogenic | 1.60 | Ambiguous | 0.6 | 1.00 | Ambiguous | 1.30 | Ambiguous | 1.47 | Destabilizing | -4.06 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 5.77 | Benign | 0.01 | Affected | 3.39 | 15 | 2 | 0 | 1.3 | -19.05 | 212.5 | 81.8 | 0.1 | 0.0 | -0.5 | 0.2 | X | Potentially Pathogenic | The guanidinium group of Arg258, located at the end of an α-β loop connecting the PH domain to the C2 domain (res. Lys251-Arg258), forms hydrogen bonds with the carboxamide groups of Asn727 and Asn729 side chains, as well as with the backbone carbonyl groups of Ala724, Leu725, and Asn727 in the WT simulations. Although the imidazole group of His258 can act as a hydrogen bond donor/acceptor, the swapped residue is unable to maintain an equally well-coordinated hydrogen bond network for linking the C2 and GAP domains in the variant simulations. | |||||||||
c.886T>G | S296A (3D Viewer) ![]() | Likely Benign | C2 | Uncertain | 1 | -6.847 | Likely Benign | 0.247 | Likely Benign | Likely Benign | 0.209 | Likely Benign | 0.50 | Ambiguous | 0.3 | -0.26 | Likely Benign | 0.12 | Likely Benign | 0.35 | Likely Benign | -1.79 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.97 | Pathogenic | 0.65 | Tolerated | 3.40 | 16 | 1 | 1 | 2.6 | -16.00 | 182.5 | 26.6 | -0.2 | 0.1 | -0.5 | 0.0 | X | Potentially Pathogenic | The hydroxyl group of the Ser296 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), stably hydrogen bonds with the carboxylate group of Asp330 in a neighboring β strand (res. Ala322-Asp332). The backbone carbonyl group of Ser296 also hydrogen bonds with the guanidinium group of Arg279 in another nearby β strand (res. Arg279-Cys285). In the variant simulations, the methyl group of the Ala296 side chain cannot hydrogen bond with Asp330, causing the carboxylate group positioning to fluctuate more than in the WT simulations.Although the residue swap does not seem to affect the anti-parallel β sheet assembly during the simulations, it is possible that the Ser296-Asp330 hydrogen bond plays a crucial role in maintaining the C2 domain fold. Notably, because Ser296 is located near the membrane interface, the potential effect of the residue swap on the SynGAP-membrane association cannot be addressed by solvent-only simulations. | |||||||||||
c.901G>A | A301T (3D Viewer) ![]() | Likely Benign | C2 | Uncertain | 5 | 6-33437806-G-A | 2 | 1.24e-6 | -3.448 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.150 | Likely Benign | 0.36 | Likely Benign | 0.2 | -0.33 | Likely Benign | 0.02 | Likely Benign | 0.03 | Likely Benign | -0.25 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 4.15 | Benign | 0.22 | Tolerated | 4.32 | 14 | 1 | 0 | -2.5 | 30.03 | 219.8 | -42.8 | -0.1 | 0.0 | -0.5 | 0.2 | Uncertain | The methyl group of Ala301, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), points outward from the β hairpin loop, and its backbone atoms do not participate in the loop formation in the WT simulations. In the variant simulations, the hydroxyl group of the Thr301 side chain also mostly points outward; however, the guanidinium group of Arg299 is moved away from its central hairpin loop position.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel. | |||||||||
c.1259T>C | F420S (3D Viewer) ![]() | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -13.231 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.544 | Likely Pathogenic | 5.34 | Destabilizing | 0.1 | 5.73 | Destabilizing | 5.54 | Destabilizing | 2.14 | Destabilizing | -7.43 | Deleterious | 0.998 | Probably Damaging | 0.938 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 3.37 | 29 | -3 | -2 | -3.6 | -60.10 | 213.3 | 57.8 | 0.0 | 0.0 | -0.4 | 0.1 | X | Potentially Pathogenic | In the WT, the phenyl ring of the Phe420 side chain, located on an α helix (res. Met414-Glu436), packs against hydrophobic residues in the interhelix area of the GAP domain (e.g., Leu689, Leu714, Leu717, Leu718). Although no large-scale adverse effects are seen in the variant simulations, the polar hydroxyl group of Ser420 is not suitable for the hydrophobic inter-helix space. Thus, the residue swap could affect protein folding. In theory, the introduced hydroxyl group could also lower the α helix integrity by H-bonding with the backbone atoms of neighboring residues in the same α helix. However, no such effect is seen in the variant simulations. | |||||||||||
c.1312G>A | A438T (3D Viewer) ![]() | Likely Benign | GAP | Conflicting | 3 | 6-33438217-G-A | 16 | 9.91e-6 | -5.339 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.021 | Likely Benign | 0.21 | Likely Benign | 0.0 | -0.07 | Likely Benign | 0.07 | Likely Benign | 0.36 | Likely Benign | -0.81 | Neutral | 0.300 | Benign | 0.011 | Benign | 4.18 | Benign | 0.14 | Tolerated | 3.38 | 26 | 1 | 0 | -2.5 | 30.03 | 214.2 | -42.7 | -0.3 | 0.1 | -0.4 | 0.1 | X | Potentially Benign | The methyl group of Ala438, located in a four-residue loop connecting two α helices (res. Asn440-Thr458 and Pro413-Glu436), packs against hydrophobic residues from a nearby α helix or loop residues (e.g., Leu703, Val699). In the variant simulations, the methyl group of Thr438 is able to establish similar hydrophobic packing. Moreover, the hydroxyl group also H-bonds with nearby residues, such as the carbonyl group of the neighboring loop residue Pro437. Accordingly, the residue swap does not generate an apparent negative effect on the protein structure based on the simulations. | ||||||||
c.1393C>G | L465V (3D Viewer) ![]() | Likely Pathogenic | GAP | Uncertain | 1 | -9.893 | Likely Pathogenic | 0.838 | Likely Pathogenic | Ambiguous | 0.276 | Likely Benign | 2.46 | Destabilizing | 0.1 | 2.66 | Destabilizing | 2.56 | Destabilizing | 1.21 | Destabilizing | -2.98 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.44 | Pathogenic | 0.10 | Tolerated | 3.37 | 34 | 2 | 1 | 0.4 | -14.03 | 204.3 | 30.9 | 0.0 | 0.0 | -0.4 | 0.6 | X | Potentially Benign | The iso-butyl side chain of Leu465, located in the middle of an α helix (res. Ala461–Phe476), packs with hydrophobic residues (e.g., Phe464, Met468, Tyr497, Ile494) in an inter-helix space formed with two other α helices (res. Ala461–Phe476 and res. Thr488-Gly502). In the variant simulations, the iso-propyl side chain of Val465 is equally sized and similarly hydrophobic as the original side chain of Leu465. Hence, the mutation does not exert any negative effects on the protein structure based on the variant simulations. | |||||||||||
c.1715G>C | W572S (3D Viewer) ![]() | Likely Pathogenic | GAP | Pathogenic | 1 | -17.461 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.775 | Likely Pathogenic | 5.78 | Destabilizing | 0.2 | 3.37 | Destabilizing | 4.58 | Destabilizing | 1.79 | Destabilizing | -12.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.24 | Pathogenic | 0.01 | Affected | 3.37 | 35 | -2 | -3 | 0.1 | -99.14 | 235.1 | 76.6 | 0.0 | 0.0 | -0.4 | 0.1 | X | Potentially Pathogenic | The introduced residue Ser572, located in an α-helix (res. Arg563-Glu578), is considerably smaller than the tryptophan it replaced. The indole ring of the Trp572 side chain lies in a hydrophobic inter-helix space, where it makes extensive hydrophobic interactions with nearby residues such as Met470, Phe569, Leu588, and Ile589. In the variant simulations, all these favorable packing interactions are completely removed, as the introduced residue Ser572 is too hydrophilic or small to fill the hydrophobic niche occupied by the indole ring. Moreover, the hydroxyl group of Ser572 forms hydrogen bonds with the carbonyl groups of Glu567 and Val568 within the same α-helix, potentially lowering its integrity. Overall, the residue swap is highly likely to cause critical protein folding problems that are underestimated based on the effects seen in the variant simulations. | |||||||||||
c.1742G>A | R581Q (3D Viewer) ![]() | Likely Pathogenic | GAP | Benign | 1 | 6-33440794-G-A | 8 | 4.96e-6 | -7.584 | In-Between | 0.673 | Likely Pathogenic | Likely Benign | 0.481 | Likely Benign | 1.31 | Ambiguous | 0.1 | -0.42 | Likely Benign | 0.45 | Likely Benign | 0.88 | Ambiguous | -2.77 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.21 | Pathogenic | 0.11 | Tolerated | 3.37 | 34 | 1 | 1 | 1.0 | -28.06 | 239.6 | 53.5 | -0.2 | 0.2 | -0.4 | 0.1 | X | Potentially Pathogenic | Arg581 is located on a short α-α loop between two α helices (res. Arg563-Glu578 and res. Glu582-Ser604). In the WT simulations, the guanidinium group of Arg581 forms salt bridges with the carboxylate groups of Asp583 within the same helix, as well as with Glu478 and/or Glu480 on a slightly α-helical loop (res. Glu478-Thr488) preceding another α helix (res. Ala461-Phe476).In the variant simulations, the neutral carboxamide group of the Gln581 side chain cannot form any of these salt bridges. Instead, it packs hydrophobically against Met477 and Ile587 or forms hydrogen bonds sporadically with nearby residues (e.g., Asp583, Arg587). Thus, although no drastic changes are observed in the variant simulations, the residue swap could weaken the tertiary structure assembly. | ||||||||
c.1862G>A | R621Q (3D Viewer) ![]() | Likely Pathogenic | GAP | Likely Benign | 1 | 6-33440914-G-A | 19 | 1.18e-5 | -14.682 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.621 | Likely Pathogenic | 0.81 | Ambiguous | 0.1 | 1.13 | Ambiguous | 0.97 | Ambiguous | 1.35 | Destabilizing | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.82 | Benign | 0.01 | Affected | 3.37 | 35 | 1 | 1 | 1.0 | -28.06 | 243.7 | 54.3 | 0.0 | 0.0 | -0.4 | 0.2 | X | X | Potentially Pathogenic | The guanidinium group of Arg621, located in an α helix (res. Glu617-Asn635), forms a salt bridge with Glu525 in a nearby loop and stacks with Leu635. In the variant simulations, the carboxamide side chain of Gln621, which can act as both a hydrogen bond acceptor and donor, also stacks with Leu635 but can only sporadically hydrogen bond with Glu525.Accordingly, the residue swap could affect the tertiary structure integrity by disrupting the salt bridge formation. Additionally, due to its location at the GAP-Ras interface, the residue swap could impact the complex formation with the GTPase, but this cannot be investigated using solvent-only simulations. | |||||||
c.662A>T | E221V (3D Viewer) ![]() | Likely Pathogenic | PH | Likely Pathogenic | 1 | -14.954 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.875 | Likely Pathogenic | -0.66 | Ambiguous | 0.2 | -0.89 | Ambiguous | -0.78 | Ambiguous | 0.49 | Likely Benign | -5.54 | Deleterious | 0.596 | Possibly Damaging | 0.203 | Benign | 5.86 | Benign | 0.00 | Affected | 3.41 | 13 | -2 | -2 | 7.7 | -29.98 | 234.5 | 50.6 | 0.0 | 0.0 | -0.4 | 0.2 | X | Uncertain | The introduced residue Val221 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the carboxylate group of Glu221, Val221 cannot form hydrogen bonds with Thr223 or a salt bridge with the amino group of the Lys207 side chain. Despite this, the WT simulations containing Glu221 do not show significant differences compared to the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||
c.670A>G | T224A (3D Viewer) ![]() | PH | Uncertain | 3 | 6-33435521-A-G | 2 | 1.24e-6 | -7.379 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | 0.464 | Likely Benign | 0.33 | Likely Benign | 0.1 | 1.05 | Ambiguous | 0.69 | Ambiguous | 0.91 | Ambiguous | -2.96 | Deleterious | 0.243 | Benign | 0.079 | Benign | 5.57 | Benign | 0.57 | Tolerated | 3.41 | 13 | 1 | 0 | 2.5 | -30.03 | 169.0 | 41.4 | -0.5 | 1.1 | -0.4 | 0.0 | X | X | Uncertain | The introduced residue Ala224 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the hydroxyl group of the Thr224 side chain in the WT model, the methyl side chain of Ala224 cannot form hydrogen bonds with nearby residues Ser204, Ser226, and Gly227. Without these hydrogen-bonding interactions at the β sheet surface, the secondary structure element becomes unstable and unfolds during the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||
c.872A>G | Y291C (3D Viewer) ![]() | Likely Pathogenic | C2 | Uncertain | 1 | -8.997 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.505 | Likely Pathogenic | 2.90 | Destabilizing | 0.4 | 3.51 | Destabilizing | 3.21 | Destabilizing | 1.35 | Destabilizing | -7.37 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.76 | Pathogenic | 0.01 | Affected | 3.38 | 23 | 0 | -2 | 3.8 | -60.04 | 205.2 | 66.1 | 0.1 | 0.0 | -0.4 | 0.4 | X | X | Potentially Pathogenic | The phenol group of the Tyr291 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), packs against hydrophobic residues of the C2 and PH domains (e.g., Leu317, Leu286, Leu284, Pro208, Val209). The phenol ring of Tyr291 also forms favorable Met-aromatic stacking with the methyl group of Met289. In the variant simulation, the thiol group of the Cys291 side chain is not as suitable for the hydrophobic inter-domain space as the phenol ring of Tyr291. Consequently, the structural unity of the PH domain is weakened and ultimately unfolds in the second simulation. Moreover, the residue swap might result in severe detrimental effects on the C2 domain structure and the C2-PH domain tertiary structure assembly during folding. | ||||||||||
c.924G>C | W308C (3D Viewer) ![]() | Likely Pathogenic | C2 | Pathogenic/Likely path. | 2 | -12.791 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.738 | Likely Pathogenic | 5.56 | Destabilizing | 0.3 | 4.38 | Destabilizing | 4.97 | Destabilizing | 1.26 | Destabilizing | -11.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.48 | Pathogenic | 0.00 | Affected | 3.38 | 19 | -8 | -2 | 3.4 | -83.07 | 230.8 | 60.5 | -0.3 | 0.1 | -0.4 | 0.4 | X | Potentially Pathogenic | The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The introduced Cys308 is smaller than the tryptophan it replaced. The thiol group of the Cys308 side chain is well-suited for the inner hydrophobic part of the C2 domain. Although the negative effects are essentially missing from the simulations, the side chain size difference between the residues is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | |||||||||||
c.953C>T | P318L (3D Viewer) ![]() | Likely Pathogenic | C2 | Uncertain | 3 | 6-33437858-C-T | 3 | 1.86e-6 | -10.090 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.624 | Likely Pathogenic | 1.33 | Ambiguous | 0.1 | 0.26 | Likely Benign | 0.80 | Ambiguous | 0.43 | Likely Benign | -8.96 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.82 | Pathogenic | 0.03 | Affected | 3.38 | 23 | -3 | -3 | 5.4 | 16.04 | 228.6 | -68.9 | -0.7 | 0.7 | -0.4 | 0.1 | X | Potentially Benign | The cyclic five-membered pyrrolidine ring of Pro318, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Asp330-Ala322, res. Thr305-Asn315), packs against the hydrophobic side chain of Ile205 at the end of the anti-parallel β sheet in the PH domain. In the variant simulations, the iso-butyl side chain of Leu318 is unable to do the same, potentially weakening the PH and C2 domain association. Importantly, the residue swap could also affect loop formation during folding, as proline can make tighter turns than leucine. Because the residue swap could affect the C2 domain stability, it could also negatively impact the SynGAP-membrane association. | ||||||||
c.1066C>T | R356C (3D Viewer) ![]() | Likely Pathogenic | C2 | Likely Benign | 1 | 6-33437971-C-T | 5 | 3.10e-6 | -11.827 | Likely Pathogenic | 0.774 | Likely Pathogenic | Likely Benign | 0.312 | Likely Benign | 0.76 | Ambiguous | 0.0 | 1.19 | Ambiguous | 0.98 | Ambiguous | 0.84 | Ambiguous | -7.12 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 1.67 | Pathogenic | 0.00 | Affected | 3.39 | 22 | -4 | -3 | 7.0 | -53.05 | 212.3 | 91.0 | -0.1 | 0.3 | -0.3 | 0.1 | X | Potentially Pathogenic | Arg356 is located in a loop that includes a short helical section and connects two anti-parallel β sheet strands (res. Gly341-Pro349, res. Thr359-Pro364). In the WT simulations, the guanidinium group of Arg356 alternately forms salt bridges with the carboxylate groups of the GAP domain residues, Glu446 and Glu698. Arg356 also forms hydrogen bonds with the hydroxyl group of the GAP domain residue Thr691 and interacts with Met409 at the C2-GAP interface.In the variant simulations, the Cys356 mutation fails to maintain any of the Arg356 interactions and only occasionally forms weak hydrogen bonds with nearby C2 domain residues (e.g., Gln407). Although no negative structural effects are observed during the simulations, Arg356 is located at the C2 and GAP domain interface, making the residue swap potentially detrimental to the tertiary structure assembly. | ||||||||
c.1193C>T | P398L (3D Viewer) ![]() | C2 | Uncertain | 1 | 6-33438098-C-T | 8 | 4.96e-6 | -7.518 | In-Between | 0.547 | Ambiguous | Likely Benign | 0.599 | Likely Pathogenic | 1.48 | Ambiguous | 0.2 | -0.54 | Ambiguous | 0.47 | Likely Benign | 0.62 | Ambiguous | -7.10 | Deleterious | 0.961 | Probably Damaging | 0.256 | Benign | 5.72 | Benign | 0.01 | Affected | 3.40 | 16 | -3 | -3 | 5.4 | 16.04 | 245.8 | -68.6 | -0.1 | 0.0 | -0.3 | 0.2 | X | Potentially Pathogenic | Pro398 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. Although the residue swap does not influence the nearby secondary structure elements, proline is often found at the ends of β sheets due to its disfavored status during folding.Additionally, the Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone. Ω loops are known to play significant roles in protein functions that require flexibility, and thus hydrophobic residues like leucine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Leu398 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. Since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
c.1286G>A | R429Q (3D Viewer) ![]() | Likely Benign | GAP | Uncertain | 2 | 6-33438191-G-A | 10 | 6.20e-6 | -8.227 | Likely Pathogenic | 0.143 | Likely Benign | Likely Benign | 0.156 | Likely Benign | 0.45 | Likely Benign | 0.1 | 0.36 | Likely Benign | 0.41 | Likely Benign | 0.98 | Ambiguous | -1.25 | Neutral | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.47 | Benign | 0.58 | Tolerated | 3.38 | 25 | 1 | 1 | 1.0 | -28.06 | 235.8 | 59.5 | 0.0 | 0.0 | -0.3 | 0.4 | X | Potentially Pathogenic | The guanidinium group of the Arg429 side chain, located in an α helix (res. Met414-Glu436), either forms a salt bridge with the carboxylate group of an acidic residue (Asp474, Asp467) or an H-bond with the hydroxyl group of Ser471 in an opposing α helix (res. Ala461-Phe476). In the variant simulations, Gln429 cannot form ionic interactions with the acidic residues; however, the carboxamide group can form multiple H-bonds. The H-bonding coordination of the Asn429 side chain varied between the replica simulations. In one simulation, three H-bonds were formed simultaneously with the Asp467 side chain, the backbone carbonyl group of Asn426, and the amide group of Met430 at the end of the same α helix. The residue swap could affect the tertiary structure assembly during folding due to weaker bond formation, but no large-scale negative effects were seen during the simulations. | ||||||||
c.1453C>T | R485C (3D Viewer) ![]() | Likely Pathogenic | GAP | Uncertain | 2 | 6-33438485-C-T | 9 | 5.58e-6 | -14.294 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.597 | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 0.26 | Likely Benign | 0.63 | Ambiguous | 0.44 | Likely Benign | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.90 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -4 | -3 | 7.0 | -53.05 | 225.5 | 99.6 | -0.1 | 0.0 | -0.3 | 0.2 | X | Uncertain | The guanidinium group of Arg485 is located in a short helical structure (res. Glu480-Leu482) within an α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. The side chain of Arg485 acts as the “arginine finger” of SynGAP, playing a crucial role in Ras-GTPase activation. Consequently, the residue swap inhibits the conversion of GTP to GDP at the enzyme’s active site. Although no negative effects on the protein structure are observed during the simulations, no definite conclusions can be drawn due to the critical role of Arg485 in GTPase activation. | ||||||||
c.1490A>G | Y497C (3D Viewer) ![]() | Likely Pathogenic | GAP | Uncertain | 1 | -11.872 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.806 | Likely Pathogenic | 3.88 | Destabilizing | 0.1 | 4.76 | Destabilizing | 4.32 | Destabilizing | 1.40 | Destabilizing | -8.82 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.65 | Pathogenic | 0.03 | Affected | 3.37 | 35 | 0 | -2 | 3.8 | -60.04 | 209.9 | 59.1 | -0.1 | 0.0 | -0.3 | 0.1 | X | X | Potentially Pathogenic | Tyr497 is located in the α-helix (res. Leu489-Glu519) within the inter-helix space of four α-helices (res. Leu489-Ile501, res. Val441-Ser457, res. Arg563-Glu578, res. Ala461-Val473). In the WT simulations, the phenol ring of Tyr497 hydrophobically packs with other residues in the inter-helix space (e.g., Leu465, Leu565, Val568). The hydroxyl group of Tyr497 also alternately forms hydrogen bonds with the carboxylate side chain of Gln456 and the backbone carbonyl of Glu564. Thus, Tyr497 plays a role in the folding and maintenance of the tertiary structure assembly between these four helices.In the variant simulations, the comparatively smaller residue, Cys497, cannot maintain any of the interactions seen with Tyr497 in the WT. Although no severe deleterious consequences are observed in the simulations, the structural effects could be more pronounced during actual protein folding. Indeed, the tertiary structure is seen to slightly break apart in the variant simulations. | ||||||||||
c.1631G>C | R544P (3D Viewer) ![]() | Likely Pathogenic | GAP | Uncertain | 2 | -16.905 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.762 | Likely Pathogenic | 4.70 | Destabilizing | 0.1 | 4.19 | Destabilizing | 4.45 | Destabilizing | 1.14 | Destabilizing | -4.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.48 | Pathogenic | 0.05 | Affected | 3.37 | 35 | 0 | -2 | 2.9 | -59.07 | 192.0 | 123.8 | 0.1 | 0.0 | -0.3 | 0.0 | X | X | Potentially Pathogenic | Arg544 is located in the middle of an α-helix (res. Ala533-Val560). In the WT simulations, the guanidinium side chain of Arg544 forms a salt bridge with the carboxylate groups of Glu548 on the same α-helix, and with Glu651 and Glu656 on an opposing α-helix (res. Glu666-Asp644). In the variant simulations, the pyrrolidine side chain of Pro544 cannot form any of the salt bridges that Arg544 does in the WT, potentially weakening the tertiary structure assembly. Additionally, Pro544 lacks the amide group, and thus, unlike Arg544 in the WT, is unable to form a hydrogen bond with the carbonyl of Gln540. This disruption breaks the continuity of the secondary structure element, causing the α-helix to bend slightly in the variant simulations. These negative structural effects could be more pronounced during protein folding and are likely to be undermined in the MD simulations. | ||||||||||
c.1652T>C | L551P (3D Viewer) ![]() | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -14.620 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.953 | Likely Pathogenic | 6.66 | Destabilizing | 0.1 | 6.58 | Destabilizing | 6.62 | Destabilizing | 2.66 | Destabilizing | -4.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.60 | Pathogenic | 0.01 | Affected | 3.37 | 35 | -3 | -3 | -5.4 | -16.04 | 208.6 | 60.9 | 0.1 | 0.0 | -0.3 | 0.0 | X | Potentially Pathogenic | L551 is located on an α-helix (res. Ala533-Val560). The iso-butyl side chain of Leu551 hydrophobically packs with nearby hydrophobic residues such as Cys547, Phe652, Leu633, and Ile630 in the inter-helix space. In the variant simulations, the pyrrolidine side chain of Pro551 is not as optimal as leucine for hydrophobic packing with the nearby residues. Moreover, Pro551 lacks the amide group, and thus, it cannot form a hydrogen bond with the backbone carbonyl group of Cys547, which disrupts the continuity of the secondary structure element. | |||||||||||
c.1786C>T | R596C (3D Viewer) ![]() | Likely Pathogenic | GAP | Conflicting | 2 | 6-33440838-C-T | 6 | 3.72e-6 | -10.805 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.633 | Likely Pathogenic | 2.94 | Destabilizing | 0.0 | 1.49 | Ambiguous | 2.22 | Destabilizing | -0.03 | Likely Benign | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.41 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -4 | -3 | 7.0 | -53.05 | 230.7 | 97.9 | -0.1 | 0.0 | -0.3 | 0.4 | X | X | Potentially Pathogenic | The guanidinium group of Arg596, located in an α helix (res. Glu582-Met603), forms a salt bridge with the carboxylate group of Glu495 from another α helix (res. Leu489-Glu519). In the WT simulations, the side chain of Arg596 hydrogen bonds with the backbone carbonyl groups of Asn487, Glu486, Arg485, and Phe484. Additionally, Arg596 can hydrogen bond with the carboxamide group of the Asn487 side chain on an opposing loop that links two α helices (res. Ala461-Arg475, res. Leu489-Glu519).In the variant simulations, the thiol group of the Cys596 side chain is unable to form salt bridges or any of the hydrogen bonds that the Arg596 side chain can. Thus, the residue swap could affect the tertiary structure assembly more profoundly than observed in the simulations. Notably, Arg596 plays a key role in positioning the aforementioned loop, which is crucial for the placement of the “arginine finger” or the Arg485 side chain during RasGTPase activation. | |||||||
c.1888A>G | I630V (3D Viewer) ![]() | GAP | Benign/Likely benign | 4 | 6-33440940-A-G | 59 | 3.66e-5 | -7.264 | In-Between | 0.145 | Likely Benign | Likely Benign | 0.143 | Likely Benign | 1.33 | Ambiguous | 0.0 | 0.94 | Ambiguous | 1.14 | Ambiguous | 0.64 | Ambiguous | -0.38 | Neutral | 0.018 | Benign | 0.011 | Benign | -1.37 | Pathogenic | 0.35 | Tolerated | 3.37 | 34 | 4 | 3 | -0.3 | -14.03 | 235.0 | 26.2 | -0.1 | 0.0 | -0.3 | 0.1 | X | Potentially Benign | The sec-butyl side chain of Ile630, located in an α helix (res. Glu617-Asn635), packs with hydrophobic residues (e.g., Phe594, Leu633, Ile626, Ile602) in the hydrophobic inter-helix space between two α helices (res. Glu617-Asn635 and res. Glu582-Met603).In the variant simulations, the iso-propyl side chain of Val630, which shares a similar size and physicochemical properties with Ile630 in the WT, maintains similar interactions in the inter-helix space. Although no negative structural effects are observed during the simulations, the implications of the residue swap on the complex formation with the GTPase, due to its location, cannot be investigated using solvent-only simulations. | |||||||||
c.1904A>G | N635S (3D Viewer) ![]() | GAP | Conflicting | 4 | 6-33440956-A-G | 10 | 6.20e-6 | -9.002 | Likely Pathogenic | 0.101 | Likely Benign | Likely Benign | 0.104 | Likely Benign | 0.80 | Ambiguous | 0.1 | 0.67 | Ambiguous | 0.74 | Ambiguous | 0.95 | Ambiguous | -4.45 | Deleterious | 0.261 | Benign | 0.044 | Benign | 3.06 | Benign | 0.05 | Affected | 3.37 | 34 | 1 | 1 | 2.7 | -27.03 | 196.0 | 30.9 | 0.1 | 0.0 | -0.3 | 0.2 | X | Uncertain | In the WT simulations, the carboxamide side chain of Asn635, located on the outer surface of an α helix (res. Glu617-Asn635), forms hydrogen bonds with Gln631 on the same α helix and with the hydroxyl side chain of Ser590 on an opposing α helix (res. Glu582-Met603).In the variant simulations, the side chain of Ser635 is shorter than asparagine and thus prefers to hydrogen bond with the carbonyl group of Gln631 on the same helix and, to a lesser extent, with Ser590 compared to Asn635 in the WT. Ser635 forms hydrogen bonds with the backbone atoms of the same helix, which may destabilize the helix, although this is not clearly evident in the simulations. The weakening of the hydrogen bond between Ser635 and Ser590 in the variant may also weaken the tertiary structure assembly between the helices.Additionally, Asn635 is at the GTPase interface. However, the implication of the residue swap on the complex formation with the GTPase cannot be investigated using solvent-only simulations. | |||||||||
c.1998G>C | E666D (3D Viewer) ![]() | Likely Pathogenic | GAP | Uncertain | 1 | -8.820 | Likely Pathogenic | 0.704 | Likely Pathogenic | Likely Benign | 0.197 | Likely Benign | 0.88 | Ambiguous | 0.0 | 0.37 | Likely Benign | 0.63 | Ambiguous | 1.05 | Destabilizing | -2.69 | Deleterious | 0.992 | Probably Damaging | 0.603 | Possibly Damaging | 3.43 | Benign | 0.06 | Tolerated | 3.38 | 28 | 3 | 2 | 0.0 | -14.03 | 237.2 | 16.5 | 0.0 | 0.0 | -0.3 | 0.1 | X | Potentially Pathogenic | The carboxylate group of Glu666, located on the α-helix (res. Ser641-Glu666), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), such as Lys566, Thr672, and Asn669, in the WT simulations. In the variant simulations, the shorter side chain of Asp666 cannot maintain these interactions as efficiently as Glu666 in the WT, resulting in a less coordinated hydrogen-bond network. | |||||||||||
c.603T>A | D201E (3D Viewer) ![]() | Likely Benign | PH | Benign | 1 | -2.640 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.165 | Likely Benign | 0.42 | Likely Benign | 0.2 | 1.99 | Ambiguous | 1.21 | Ambiguous | 0.23 | Likely Benign | -0.69 | Neutral | 0.633 | Possibly Damaging | 0.108 | Benign | 4.30 | Benign | 1.00 | Tolerated | 3.46 | 9 | 3 | 2 | 0.0 | 14.03 | 258.7 | -24.8 | 0.9 | 0.1 | -0.3 | 0.2 | X | Uncertain | Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||
c.603T>G | D201E (3D Viewer) ![]() | Likely Benign | PH | Conflicting | 2 | 6-33435245-T-G | 20 | 1.24e-5 | -2.640 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.165 | Likely Benign | 0.42 | Likely Benign | 0.2 | 1.99 | Ambiguous | 1.21 | Ambiguous | 0.23 | Likely Benign | -0.69 | Neutral | 0.633 | Possibly Damaging | 0.108 | Benign | 4.30 | Benign | 1.00 | Tolerated | 3.46 | 9 | 3 | 2 | 0.0 | 14.03 | 258.7 | -24.8 | 0.9 | 0.1 | -0.3 | 0.2 | X | Uncertain | Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||
c.1025A>C | Y342S (3D Viewer) ![]() | Likely Pathogenic | C2 | Uncertain | 2 | -7.996 | In-Between | 0.925 | Likely Pathogenic | Ambiguous | 0.407 | Likely Benign | 3.03 | Destabilizing | 0.1 | 2.87 | Destabilizing | 2.95 | Destabilizing | 0.93 | Ambiguous | -6.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.75 | Pathogenic | 0.04 | Affected | 3.37 | 25 | -3 | -2 | 0.5 | -76.10 | 200.1 | 77.8 | 0.0 | 0.0 | -0.2 | 0.1 | Potentially Pathogenic | The phenol ring of Tyr342, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), faces outward in the C2 domain. In the WT simulations, the phenol ring of Tyr342 contributes to a triple tyrosine stack (Tyr342, Tyr328, and Tyr281) that links together three anti-parallel β sheet strands. Additionally, it shields Gly344 from the solvent, reducing its exposure and providing stability for the β-sandwich. This motif also contributes to a twist formation in the β sheet.In the variant simulations, the Ser342 side chain cannot participate in the stack formation. Instead, the hydroxyl group of the Ser342 side chain forms a hydrogen bond with the imidazole ring of His326 in a neighboring β strand (res. Ala322-Asp330). This disrupts the formation of a hydrogen bond between His326 and the carboxylate group of the Glu283 side chain from another β strand (res. Arg279-Cys285). Although these changes in surface interactions could weaken the characteristic twist that strengthens the β sheet fold, no major structural effects are observed in the variant simulations. The residue swap could also affect the SynGAP-membrane association, as the hydroxyl group of Ser342 could form hydrogen bonds with membrane-facing loop residues. However, this phenomenon cannot be addressed using solvent-only simulations. | ||||||||||||
c.1027G>A | V343I (3D Viewer) ![]() | Likely Benign | C2 | Uncertain | 2 | 6-33437932-G-A | 1 | 6.20e-7 | -6.020 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.020 | Likely Benign | -0.27 | Likely Benign | 0.0 | -0.04 | Likely Benign | -0.16 | Likely Benign | -0.39 | Likely Benign | -0.14 | Neutral | 0.159 | Benign | 0.084 | Benign | 1.98 | Pathogenic | 0.27 | Tolerated | 3.37 | 25 | 4 | 3 | 0.3 | 14.03 | 240.2 | -26.9 | -0.2 | 0.2 | -0.2 | 0.2 | X | Potentially Benign | The iso-propyl side chain of Val343, located in an anti-parallel β sheet strand (res. Gly341-Pro349), is packing against multiple hydrophobic residues of the C2 domain (e.g., Leu327, Leu274, Val365). In the variant simulations, the sec-butyl side chain of Ile343 is basically able to form the same interactions as valine due to its similar hydrophobic profile. The residue swap also does not seem to cause negative effects on the protein structure based on the simulations. | ||||||||
c.1231A>G | I411V (3D Viewer) ![]() | Likely Benign | GAP | Likely Benign | 1 | -6.290 | Likely Benign | 0.385 | Ambiguous | Likely Benign | 0.212 | Likely Benign | 0.74 | Ambiguous | 0.0 | 0.82 | Ambiguous | 0.78 | Ambiguous | 0.99 | Ambiguous | -0.86 | Neutral | 0.935 | Possibly Damaging | 0.858 | Possibly Damaging | 3.90 | Benign | 0.27 | Tolerated | 3.38 | 28 | 4 | 3 | -0.3 | -14.03 | 233.3 | 28.2 | -0.2 | 0.0 | -0.2 | 0.0 | X | Potentially Benign | The sec-butyl side chain of Ile411, located in the hydrophobic space between an anti-parallel β sheet strand (res. Pro398-Ile411) and an α helix (res. Asp684-Gln702), packs against multiple residues (e.g., Met409, Arg259). In the variant simulations, the side chain of Val411 is able to favorably fill the same hydrophobic niche despite its slightly smaller size. In short, the residue swap has no apparent negative effect on the structure based on the simulations. | |||||||||||
c.1150G>A | G384S (3D Viewer) ![]() | Likely Benign | C2 | Uncertain | 1 | 6-33438055-G-A | 1 | 6.22e-7 | -5.243 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.315 | Likely Benign | 1.92 | Ambiguous | 0.2 | 1.66 | Ambiguous | 1.79 | Ambiguous | 0.19 | Likely Benign | -0.67 | Neutral | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 1.33 | Pathogenic | 0.04 | Affected | 4.32 | 2 | 1 | 0 | -0.4 | 30.03 | 202.4 | -49.8 | 0.5 | 1.0 | -0.2 | 0.0 | Uncertain | Gly384 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and so they are rich in glycines, prolines, and, to a lesser extent, small hydrophilic residues to ensure maximum flexibility. Thus, the variant’s Ser384 is potentially tolerated in the Ω loop, although the hydroxyl group of Ser384 forms various hydrogen bonds with several other loop residues in the variant simulations. However, since the effects on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
c.1213C>T | R405C (3D Viewer) ![]() | Likely Pathogenic | C2 | Conflicting | 2 | 6-33438118-C-T | 6 | 3.72e-6 | -9.206 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 0.427 | Likely Benign | 0.72 | Ambiguous | 0.1 | 1.51 | Ambiguous | 1.12 | Ambiguous | 1.21 | Destabilizing | -7.27 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.61 | Benign | 0.02 | Affected | 3.38 | 28 | -4 | -3 | 7.0 | -53.05 | 221.3 | 82.6 | -0.1 | 0.0 | -0.2 | 0.3 | X | X | Potentially Pathogenic | The guanidinium group of Arg405, located in an anti-parallel β sheet strand of the C2 domain (res. Ala399-Ile411), forms a salt bridge with the carboxylate group of the Glu446 side chain from an opposing α helix (res. Val441-Ser457) in the GAP domain. The positively charged Arg405 side chain also stacks with the aromatic ring of the Phe358 side chain from a loop preceding the β strand (res. Thr359-Thr366), which could assist in maintaining the anti-parallel strand arrangement.In the variant simulations, the thiol-containing side chain of Cys405 is neutral and smaller compared to the arginine side chain. The lack of Arg405-Phe358 stacking affects the loop structure, causing it to assume a β strand form—an effect that could be exacerbated during protein folding. Moreover, the inability of Cys405 to form a salt bridge with Glu446 could affect the tertiary structure assembly, although this is not apparent based on the variant simulations. | |||||||
c.1606T>G | L536V (3D Viewer) ![]() | Likely Pathogenic | GAP | Uncertain | 1 | -9.014 | Likely Pathogenic | 0.269 | Likely Benign | Likely Benign | 0.586 | Likely Pathogenic | 1.25 | Ambiguous | 0.3 | 1.22 | Ambiguous | 1.24 | Ambiguous | 1.20 | Destabilizing | -2.81 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.34 | Pathogenic | 0.09 | Tolerated | 3.37 | 34 | 2 | 1 | 0.4 | -14.03 | 204.7 | 26.4 | 0.2 | 0.0 | -0.2 | 0.2 | X | Potentially Benign | Leu536 is located on an α-helix (res. Ala533-Val560) at the membrane interface. The iso-butyl group of Leu536 interacts with nearby hydrophobic residues in the preceding loop (e.g., Val526, Pro528, Cys531). In the variant simulations, the iso-propyl side chain of Val536 forms similar hydrophobic interactions as Leu536 in the WT, causing no negative structural effects. | |||||||||||
c.1306G>A | E436K (3D Viewer) ![]() | Likely Pathogenic | GAP | Uncertain | 1 | -13.869 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.829 | Likely Pathogenic | 0.56 | Ambiguous | 0.1 | 2.86 | Destabilizing | 1.71 | Ambiguous | 0.82 | Ambiguous | -3.77 | Deleterious | 0.994 | Probably Damaging | 0.951 | Probably Damaging | 4.71 | Benign | 0.02 | Affected | 3.37 | 29 | 0 | 1 | -0.4 | -0.94 | 186.8 | 39.8 | 0.0 | 0.0 | -0.2 | 0.0 | X | X | X | Potentially Pathogenic | The carboxylate group of Glu436, located on the α helix (res. Met414-Glu436), forms a salt bridge with the amino group of the Lys444 side chain on an opposing α helix (res. Val441-Ser457). The backbone carbonyl of Glu436 also H-bonds with the Lys444 side chain, which helps keep the ends of the two α helices tightly connected. In contrast, in the variant simulations, the salt bridge formation with Lys444 is not possible. Instead, the repelled Lys436 side chain rotates outward, causing a change in the α helix backbone H-bonding: the amide group of Lys444 H-bonds with the carbonyl of Ala433 instead of the carbonyl of Cys432. | |||||||||
c.1394T>C | L465P (3D Viewer) ![]() | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -14.824 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.778 | Likely Pathogenic | 7.18 | Destabilizing | 0.3 | 10.85 | Destabilizing | 9.02 | Destabilizing | 2.73 | Destabilizing | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 3.37 | 34 | -3 | -3 | -5.4 | -16.04 | 211.1 | 65.9 | 0.1 | 0.0 | -0.2 | 0.0 | X | Potentially Pathogenic | The iso-butyl side chain of Leu465, located in the middle of an α helix (res. Ala461–Phe476), packs with hydrophobic residues (e.g., Phe464, Met468, Tyr497, Ile494) in an inter-helix space formed with two other α helices (res. Ala461–Phe476 and res. Thr488-Gly502). In the variant simulations, the cyclic five-membered pyrrolidine ring of Pro465 is not as optimal as the side chain of Leu465 for filling the three α helix hydrophobic niche. Although the residue swap does not cause a large-scale conformational shift during the simulations, the H-bond between the backbone amide group of Leu465 and the backbone carbonyl group of Ala461 is lost. This, in turn, breaks the continuity of the α helix secondary structure element. | |||||||||||
c.1409T>C | M470T (3D Viewer) ![]() | Likely Pathogenic | GAP | Uncertain | 1 | -8.104 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.763 | Likely Pathogenic | 3.19 | Destabilizing | 0.1 | 2.68 | Destabilizing | 2.94 | Destabilizing | 1.49 | Destabilizing | -5.30 | Deleterious | 0.996 | Probably Damaging | 0.985 | Probably Damaging | -1.08 | Pathogenic | 0.24 | Tolerated | 3.37 | 34 | -1 | -1 | -2.6 | -30.09 | 213.8 | 46.5 | 0.0 | 0.0 | -0.2 | 0.2 | X | X | Potentially Pathogenic | The thioether group of Met470, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues in the inter-helix space (e.g., Val473, Leu558, Cys576, Trp572) formed by two other α helices (res. Ser604–Arg581, res. Pro562–Arg579). In the WT simulations, the Met470 side chain also packs against the positively charged guanidinium groups of Arg575, Arg429, and Arg579, which form salt bridges with the negatively charged carboxylate groups of the Asp474 and Asp467 side chains at the protein surface. In the variant simulations, the hydroxyl group of the Thr470 side chain forms an H-bond with the backbone carbonyl group of Ser466 in the α helix, potentially lowering its structural integrity. Importantly, the hydroxyl group of Thr470 also forms an H-bond with the guanidinium group of Arg575, which helps it form a more permanent salt bridge with Asp467. | ||||||||||
c.1428C>G | F476L (3D Viewer) ![]() | GAP | Uncertain | 2 | 6-33438460-C-G | 4 | 2.48e-6 | -10.109 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.180 | Likely Benign | 1.00 | Ambiguous | 0.1 | 1.04 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | -1.10 | Neutral | 0.997 | Probably Damaging | 0.978 | Probably Damaging | 3.53 | Benign | 0.60 | Tolerated | 3.40 | 22 | 2 | 0 | 1.0 | -34.02 | 235.9 | 16.1 | 0.0 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | In the WT simulations, the phenyl ring of Phe476, located at the end of an α-helix (res. Ala461-Phe476), packs with the hydrophobic side chains of Leu482 and Ile483. Additionally, Phe476 stacks with the Arg475 side chain on the preceding α-α loop connecting the two α-helices (res. Ala461-Phe476 and res. Leu489-Glu519) near the GAP-Ras interface.In the variant simulations, Leu476 can maintain hydrophobic packing with neighboring residues, although not as efficiently as the phenylalanine in the WT system. The absence of Phe476/Arg475 stacking weakens the integrity of the α-helix end in the variant simulations. Nonetheless, no large-scale adverse effects are observed in the simulations. Lastly, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. |
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