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.2651G>A | R884Q![]() | Likely Benign | Uncertain | 2 | 6-33443203-G-A | 5 | 3.10e-6 | -3.785 | Likely Benign | 0.128 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.42 | Neutral | 0.012 | Benign | 0.004 | Benign | 2.62 | Benign | 0.36 | Tolerated | 4.32 | 4 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
c.2669G>A | R890H![]() | Likely Benign | Benign | 1 | 6-33443221-G-A | 19 | 1.18e-5 | -3.600 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -1.29 | Neutral | 0.254 | Benign | 0.134 | Benign | 3.97 | Benign | 0.15 | Tolerated | 4.32 | 4 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||
c.2669G>C | R890P![]() | Likely Benign | Likely Benign | 2 | 6-33443221-G-C | 28 | 1.74e-5 | -1.931 | Likely Benign | 0.301 | Likely Benign | Likely Benign | 0.191 | Likely Benign | -1.21 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 4.02 | Benign | 0.28 | Tolerated | 4.32 | 4 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||
c.2684G>A | S895N![]() | Likely Benign | Uncertain | 1 | -6.399 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 0.118 | Likely Benign | -0.85 | Neutral | 0.991 | Probably Damaging | 0.988 | Probably Damaging | 2.64 | Benign | 0.30 | Tolerated | 4.32 | 4 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||
c.2695A>G | I899V![]() | Likely Benign | Benign | 1 | 6-33443247-A-G | 6 | 3.72e-6 | -2.569 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.040 | Likely Benign | 0.09 | Neutral | 0.220 | Benign | 0.078 | Benign | 2.75 | Benign | 0.92 | Tolerated | 4.32 | 4 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||
c.2699C>T | T900M![]() | Likely Benign | Conflicting | 2 | 6-33443251-C-T | 14 | 8.68e-6 | -3.852 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.015 | Likely Benign | -0.81 | Neutral | 0.060 | Benign | 0.016 | Benign | 2.79 | Benign | 0.08 | Tolerated | 4.32 | 4 | -1 | -1 | 2.6 | 30.09 | |||||||||||||||||||||||||||
c.2702C>T | A901V![]() | Likely Benign | Uncertain | 2 | 6-33443254-C-T | 2 | 1.24e-6 | -5.043 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -1.83 | Neutral | 0.106 | Benign | 0.009 | Benign | 2.64 | Benign | 0.17 | Tolerated | 3.77 | 5 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||
c.2710A>G | M904V![]() | Likely Benign | Likely Benign | 2 | 6-33443262-A-G | 77 | 4.78e-5 | -2.907 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.33 | Neutral | 0.039 | Benign | 0.023 | Benign | 2.80 | Benign | 0.10 | Tolerated | 3.77 | 5 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||
c.2711T>C | M904T![]() | Likely Benign | Uncertain | 1 | -2.721 | Likely Benign | 0.668 | Likely Pathogenic | Likely Benign | 0.042 | Likely Benign | -1.15 | Neutral | 0.277 | Benign | 0.103 | Benign | 2.78 | Benign | 0.18 | Tolerated | 3.77 | 5 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||
c.2714G>A | R905H![]() | Likely Benign | Uncertain | 1 | 6-33443266-G-A | 8 | 4.96e-6 | -4.182 | Likely Benign | 0.457 | Ambiguous | Likely Benign | 0.192 | Likely Benign | -1.11 | Neutral | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 2.59 | Benign | 0.09 | Tolerated | 3.77 | 5 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||
c.2729G>C | G910A![]() | Likely Benign | Uncertain | 1 | 6-33443281-G-C | 1 | 6.20e-7 | -3.587 | Likely Benign | 0.361 | Ambiguous | Likely Benign | 0.209 | Likely Benign | -1.43 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 2.78 | Benign | 0.10 | Tolerated | 3.77 | 5 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||
c.2743G>A | G915S![]() | Likely Benign | Benign | 1 | 6-33443295-G-A | 9 | 5.58e-6 | -3.557 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -0.88 | Neutral | 0.801 | Possibly Damaging | 0.201 | Benign | 2.73 | Benign | 0.31 | Tolerated | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
c.2765G>A | R922Q![]() | Likely Benign | Benign | 1 | 6-33443317-G-A | 7 | 4.34e-6 | -3.295 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.27 | Neutral | 0.992 | Probably Damaging | 0.736 | Possibly Damaging | 2.57 | Benign | 0.20 | Tolerated | 3.77 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
c.2768T>A | I923N![]() | Likely Benign | Uncertain | 1 | -0.733 | Likely Benign | 0.712 | Likely Pathogenic | Likely Benign | 0.108 | Likely Benign | -1.16 | Neutral | 0.991 | Probably Damaging | 0.793 | Possibly Damaging | 2.70 | Benign | 0.13 | Tolerated | 3.77 | 5 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||
c.2809G>C | D937H![]() | Likely Benign | Uncertain | 1 | -0.733 | Likely Benign | 0.677 | Likely Pathogenic | Likely Benign | 0.150 | Likely Benign | -1.74 | Neutral | 1.000 | Probably Damaging | 0.975 | Probably Damaging | 2.68 | Benign | 0.13 | Tolerated | 3.77 | 5 | -1 | 1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||
c.2812G>A | G938R![]() | Likely Benign | Uncertain | 1 | -5.271 | Likely Benign | 0.732 | Likely Pathogenic | Likely Benign | 0.141 | Likely Benign | -1.11 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.74 | Benign | 0.36 | Tolerated | 3.77 | 5 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
c.2818G>A | G940S![]() | Likely Benign | Uncertain | 1 | 6-33443370-G-A | 1 | 6.20e-7 | -5.451 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.135 | Likely Benign | 0.45 | Neutral | 0.409 | Benign | 0.253 | Benign | 2.77 | Benign | 0.44 | Tolerated | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
c.2818G>C | G940R![]() | Likely Benign | Benign | 1 | 6-33443370-G-C | 5 | 3.10e-6 | -6.169 | Likely Benign | 0.480 | Ambiguous | Likely Benign | 0.060 | Likely Benign | 0.02 | Neutral | 0.922 | Possibly Damaging | 0.543 | Possibly Damaging | 2.73 | Benign | 0.15 | Tolerated | 3.77 | 5 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||
c.2835T>A | H945Q![]() | Likely Benign | Conflicting | 2 | 6-33443387-T-A | 3 | 1.86e-6 | -5.248 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.343 | Likely Benign | -0.36 | Neutral | 0.995 | Probably Damaging | 0.939 | Probably Damaging | 5.03 | Benign | 0.06 | Tolerated | 4.32 | 4 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||
c.2840G>C | G947A![]() | Likely Benign | Likely Benign | 1 | 6-33443392-G-C | 28 | 1.73e-5 | -6.511 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -0.41 | Neutral | 0.224 | Benign | 0.131 | Benign | 4.97 | Benign | 0.10 | Tolerated | 4.32 | 4 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||
c.2852A>G | H951R![]() | Likely Benign | Likely Pathogenic | 1 | -4.964 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.185 | Likely Benign | -1.08 | Neutral | 0.048 | Benign | 0.029 | Benign | 5.46 | Benign | 0.24 | Tolerated | 3.77 | 5 | 2 | 0 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||
c.2854G>A | G952S![]() | Likely Benign | Conflicting | 2 | 6-33443406-G-A | 2 | 1.24e-6 | -6.190 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.167 | Likely Benign | 0.19 | Neutral | 0.000 | Benign | 0.002 | Benign | 3.31 | Benign | 0.07 | Tolerated | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
c.2858C>A | P953Q![]() | Likely Benign | Uncertain | 1 | -6.038 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -0.78 | Neutral | 0.058 | Benign | 0.015 | Benign | 2.78 | Benign | 0.29 | Tolerated | 3.77 | 5 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||
c.2860C>T | P954S![]() | Likely Benign | Likely Benign | 1 | 6-33443412-C-T | 1 | 6.20e-7 | -3.525 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.25 | Neutral | 0.954 | Possibly Damaging | 0.812 | Possibly Damaging | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||
c.2873A>C | H958P![]() | Likely Benign | Benign | 1 | 6-33443425-A-C | 2 | 1.24e-6 | -8.369 | Likely Pathogenic | 0.068 | Likely Benign | Likely Benign | 0.204 | Likely Benign | -0.36 | Neutral | 0.925 | Possibly Damaging | 0.316 | Benign | 4.14 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||
c.2881C>T | H961Y![]() | Likely Benign | Conflicting | 2 | 6-33443433-C-T | 3 | 1.86e-6 | -8.051 | Likely Pathogenic | 0.157 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -1.07 | Neutral | 0.716 | Possibly Damaging | 0.147 | Benign | 4.10 | Benign | 0.55 | Tolerated | 3.77 | 5 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||
c.2888A>G | H963R![]() | Likely Benign | Uncertain | 1 | 6-33443440-A-G | 8 | 4.96e-6 | -8.952 | Likely Pathogenic | 0.169 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -1.28 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.15 | Benign | 0.24 | Tolerated | 3.77 | 5 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||
c.2900G>A | R967Q![]() | Likely Benign | Benign/Likely benign | 2 | 6-33443452-G-A | 31 | 1.92e-5 | -3.057 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -0.01 | Neutral | 0.994 | Probably Damaging | 0.626 | Possibly Damaging | 4.21 | Benign | 0.36 | Tolerated | 4.32 | 2 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
c.2900G>T | R967L![]() | Likely Benign | Uncertain | 1 | 6-33443452-G-T | 1 | 6.20e-7 | -3.496 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.99 | Neutral | 0.959 | Probably Damaging | 0.586 | Possibly Damaging | 4.15 | Benign | 0.75 | Tolerated | 4.32 | 2 | -2 | -3 | 8.3 | -43.03 | |||||||||||||||||||||||||||
c.2909A>G | E970G![]() | Likely Benign | Benign | 1 | -0.167 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -0.93 | Neutral | 0.144 | Benign | 0.058 | Benign | 4.09 | Benign | 0.10 | Tolerated | 4.32 | 2 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||
c.2914C>G | P972A![]() | Likely Benign | Uncertain | 1 | 6-33443466-C-G | 1 | 6.20e-7 | -0.167 | Likely Benign | 0.045 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -0.89 | Neutral | 0.016 | Benign | 0.011 | Benign | 4.29 | Benign | 0.07 | Tolerated | 4.32 | 2 | -1 | 1 | 3.4 | -26.04 | |||||||||||||||||||||||||||
c.2924C>A | T975N![]() | Likely Benign | Uncertain | 1 | 6-33443476-C-A | 1 | 6.20e-7 | -4.671 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -0.58 | Neutral | 0.586 | Possibly Damaging | 0.302 | Benign | 4.13 | Benign | 0.07 | Tolerated | 4.32 | 2 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||
c.2924C>G | T975S![]() | Likely Benign | Uncertain | 1 | -2.743 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -0.57 | Neutral | 0.059 | Benign | 0.061 | Benign | 4.16 | Benign | 0.20 | Tolerated | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||||
c.2924C>T | T975I![]() | Likely Benign | Uncertain | 1 | 6-33443476-C-T | 6 | 3.72e-6 | -3.912 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -1.66 | Neutral | 0.411 | Benign | 0.239 | Benign | 4.11 | Benign | 0.66 | Tolerated | 4.32 | 2 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||
c.2928T>G | F976L![]() | Likely Benign | Uncertain | 1 | -2.432 | Likely Benign | 0.825 | Likely Pathogenic | Ambiguous | 0.212 | Likely Benign | -0.87 | Neutral | 0.264 | Benign | 0.102 | Benign | 4.20 | Benign | 0.53 | Tolerated | 4.32 | 2 | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||
c.2932C>T | P978S![]() | Likely Benign | Uncertain | 1 | -3.913 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.07 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 4.22 | Benign | 0.48 | Tolerated | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
c.2935T>C | F979L![]() | Likely Benign | Uncertain | 1 | -2.341 | Likely Benign | 0.870 | Likely Pathogenic | Ambiguous | 0.228 | Likely Benign | -1.00 | Neutral | 0.625 | Possibly Damaging | 0.430 | Benign | 4.22 | Benign | 0.73 | Tolerated | 4.32 | 2 | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||
c.2960A>G | D987G![]() | Likely Pathogenic | Uncertain | 1 | -4.782 | Likely Benign | 0.849 | Likely Pathogenic | Ambiguous | 0.234 | Likely Benign | -2.79 | Deleterious | 0.943 | Possibly Damaging | 0.808 | Possibly Damaging | 2.45 | Pathogenic | 0.07 | Tolerated | 4.32 | 2 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||
c.2998A>G | I1000V![]() | Likely Benign | Uncertain | 2 | -4.102 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -0.20 | Neutral | 0.437 | Benign | 0.170 | Benign | 2.76 | Benign | 0.81 | Tolerated | 4.32 | 4 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||
c.3041G>T | G1014V![]() | Likely Benign | Uncertain | 1 | -4.612 | Likely Benign | 0.181 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -2.47 | Neutral | 0.818 | Possibly Damaging | 0.377 | Benign | 2.72 | Benign | 0.06 | Tolerated | 3.77 | 5 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||
c.3048C>A | D1016E![]() | Likely Benign | Likely Benign | 1 | 6-33443600-C-A | 2 | 1.24e-6 | -3.422 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.017 | Likely Benign | -0.37 | Neutral | 0.008 | Benign | 0.028 | Benign | 2.64 | Benign | 0.65 | Tolerated | 3.77 | 5 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||
c.3049T>C | F1017L![]() | Likely Benign | Benign | 1 | -2.048 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | -2.38 | Neutral | 0.798 | Possibly Damaging | 0.373 | Benign | 2.65 | Benign | 0.72 | Tolerated | 3.77 | 5 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||
c.3092T>C | M1031T![]() | Likely Benign | Uncertain | 1 | 6-33443644-T-C | 2 | 1.24e-6 | -1.863 | Likely Benign | 0.540 | Ambiguous | Likely Benign | 0.085 | Likely Benign | -0.24 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.67 | Benign | 1.00 | Tolerated | 3.77 | 5 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||
c.3100C>G | P1034A![]() | Likely Benign | Benign | 1 | -4.174 | Likely Benign | 0.178 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -2.44 | Neutral | 0.059 | Benign | 0.061 | Benign | 2.47 | Pathogenic | 0.06 | Tolerated | 3.77 | 5 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||
c.3103C>A | P1035T![]() | Likely Benign | Uncertain | 1 | -4.447 | Likely Benign | 0.426 | Ambiguous | Likely Benign | 0.087 | Likely Benign | -0.96 | Neutral | 0.901 | Possibly Damaging | 0.537 | Possibly Damaging | 2.72 | Benign | 0.23 | Tolerated | 3.77 | 5 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||
c.3116T>C | I1039T![]() | Likely Benign | Uncertain | 1 | 6-33443668-T-C | 12 | 7.43e-6 | -2.465 | Likely Benign | 0.645 | Likely Pathogenic | Likely Benign | 0.193 | Likely Benign | 0.45 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.75 | Benign | 0.10 | Tolerated | 3.77 | 5 | -1 | 0 | -5.2 | -12.05 | |||||||||||||||||||||||||||
c.3121C>T | P1041S![]() | Likely Benign | Conflicting | 2 | 6-33443673-C-T | 1 | 6.20e-7 | -4.246 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.344 | Likely Benign | -2.72 | Deleterious | 0.664 | Possibly Damaging | 0.283 | Benign | 5.48 | Benign | 0.11 | Tolerated | 3.77 | 5 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||
c.3125A>G | Q1042R![]() | Likely Benign | Uncertain | 2 | 6-33443677-A-G | 2 | 1.24e-6 | -2.928 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.300 | Likely Benign | -1.39 | Neutral | 0.586 | Possibly Damaging | 0.120 | Benign | 5.48 | Benign | 0.12 | Tolerated | 3.77 | 5 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||
c.3134C>G | A1045G![]() | Likely Benign | Benign/Likely benign | 7 | 6-33443686-C-G | 1407 | 8.72e-4 | -3.246 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.024 | Likely Benign | -1.21 | Neutral | 0.224 | Benign | 0.066 | Benign | 2.64 | Benign | 0.33 | Tolerated | 3.77 | 5 | 1 | 0 | -2.2 | -14.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||
c.3136C>G | P1046A![]() | Likely Benign | Uncertain | 1 | 6-33443688-C-G | 1 | 6.20e-7 | -3.246 | Likely Benign | 0.048 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -1.67 | Neutral | 0.001 | Benign | 0.008 | Benign | 2.39 | Pathogenic | 0.29 | Tolerated | 3.77 | 5 | -1 | 1 | 3.4 | -26.04 | |||||||||||||||||||||||||||
c.3142G>C | G1048R![]() | Likely Benign | Uncertain | 1 | -4.305 | Likely Benign | 0.435 | Ambiguous | Likely Benign | 0.503 | Likely Pathogenic | -0.54 | Neutral | 0.919 | Possibly Damaging | 0.728 | Possibly Damaging | 2.54 | Benign | 0.10 | Tolerated | 3.77 | 5 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
c.3151G>T | G1051C![]() | Likely Pathogenic | 1 | -9.050 | Likely Pathogenic | 0.122 | Likely Benign | Likely Benign | 0.497 | Likely Benign | -0.90 | Neutral | 0.971 | Probably Damaging | 0.750 | Possibly Damaging | -0.74 | Pathogenic | 0.10 | Tolerated | 3.77 | 5 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||
c.3152G>A | G1051D![]() | Benign | 1 | 6-33443704-G-A | 2 | 1.24e-6 | -9.379 | Likely Pathogenic | 0.311 | Likely Benign | Likely Benign | 0.445 | Likely Benign | -0.31 | Neutral | 0.761 | Possibly Damaging | 0.239 | Benign | -0.74 | Pathogenic | 0.39 | Tolerated | 3.77 | 5 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||
c.3154G>A | G1052R![]() | Uncertain | 1 | -9.050 | Likely Pathogenic | 0.383 | Ambiguous | Likely Benign | 0.497 | Likely Benign | -0.41 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 3.90 | Benign | 0.10 | Tolerated | 3.77 | 5 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||
c.3160G>A | G1054S![]() | Likely Benign | Benign | 1 | 6-33443712-G-A | 32 | 1.99e-5 | -5.294 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.160 | Likely Benign | 0.21 | Neutral | 0.121 | Benign | 0.013 | Benign | 4.04 | Benign | 0.63 | Tolerated | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
c.3161G>A | G1054D![]() | Uncertain | 1 | -10.385 | Likely Pathogenic | 0.351 | Ambiguous | Likely Benign | 0.279 | Likely Benign | -0.26 | Neutral | 0.818 | Possibly Damaging | 0.266 | Benign | 4.07 | Benign | 0.37 | Tolerated | 3.77 | 5 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||
c.3170G>A | S1057N![]() | Likely Benign | Uncertain | 1 | -6.386 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.218 | Likely Benign | -0.41 | Neutral | 0.451 | Benign | 0.129 | Benign | 5.25 | Benign | 0.28 | Tolerated | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||
c.3178G>A | G1060S![]() | Likely Benign | Uncertain | 1 | 6-33443730-G-A | -4.759 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.376 | Likely Benign | -0.08 | Neutral | 0.271 | Benign | 0.054 | Benign | 2.69 | Benign | 0.49 | Tolerated | 4.32 | 2 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
c.3179G>T | G1060V![]() | Likely Benign | Benign | 1 | 6-33443731-G-T | 1 | 6.22e-7 | -6.966 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.369 | Likely Benign | -0.73 | Neutral | 0.986 | Probably Damaging | 0.728 | Possibly Damaging | 2.63 | Benign | 0.33 | Tolerated | 4.32 | 2 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||
c.3209G>A | R1070K![]() | Likely Benign | Conflicting | 2 | -5.093 | Likely Benign | 0.326 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.42 | Neutral | 0.049 | Benign | 0.048 | Benign | 3.86 | Benign | 0.09 | Tolerated | 3.77 | 5 | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||
c.3223C>A | Q1075K![]() | Likely Benign | Uncertain | 1 | -5.135 | Likely Benign | 0.728 | Likely Pathogenic | Likely Benign | 0.134 | Likely Benign | -0.67 | Neutral | 0.963 | Probably Damaging | 0.959 | Probably Damaging | 2.75 | Benign | 1.00 | Tolerated | 3.77 | 5 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||
c.3238G>A | A1080T![]() | Likely Benign | Conflicting | 2 | 6-33443790-G-A | 17 | 1.06e-5 | -3.928 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.144 | Likely Benign | -0.19 | Neutral | 0.253 | Benign | 0.042 | Benign | 4.10 | Benign | 0.60 | Tolerated | 3.77 | 5 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||
c.3238G>T | A1080S![]() | Likely Benign | Uncertain | 1 | 6-33443790-G-T | 1 | 6.26e-7 | -3.277 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 0.01 | Neutral | 0.702 | Possibly Damaging | 0.346 | Benign | 4.16 | Benign | 0.08 | Tolerated | 3.77 | 5 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||
c.323A>G | K108R![]() | Likely Benign | Uncertain | 1 | 6-33432188-A-G | 6 | 3.72e-6 | -2.892 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.184 | Likely Benign | 0.37 | Neutral | 0.993 | Probably Damaging | 0.956 | Probably Damaging | 4.22 | Benign | 1.00 | Tolerated | 3.61 | 5 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||
c.3250C>G | P1084A![]() | Likely Benign | Uncertain | 1 | -3.928 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -2.54 | Deleterious | 0.649 | Possibly Damaging | 0.157 | Benign | 4.05 | Benign | 0.35 | Tolerated | 3.77 | 5 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||
c.3287A>C | E1096A![]() | Likely Benign | Uncertain | 1 | -4.504 | Likely Benign | 0.510 | Ambiguous | Likely Benign | 0.164 | Likely Benign | -1.37 | Neutral | 0.626 | Possibly Damaging | 0.184 | Benign | 2.77 | Benign | 0.16 | Tolerated | 3.77 | 5 | -1 | 0 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||
c.3293G>A | S1098N![]() | Likely Benign | Conflicting | 2 | 6-33443845-G-A | 6 | 3.89e-6 | -5.120 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.58 | Neutral | 0.369 | Benign | 0.120 | Benign | 2.76 | Benign | 0.36 | Tolerated | 3.77 | 5 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||
c.3304G>A | A1102T![]() | Likely Benign | Uncertain | 1 | 6-33443856-G-A | 11 | 7.17e-6 | -3.540 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.30 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.32 | Pathogenic | 0.95 | Tolerated | 3.77 | 5 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||
c.3304G>C | A1102P![]() | Likely Benign | Uncertain | 1 | -5.120 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -0.97 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.26 | Pathogenic | 0.13 | Tolerated | 3.77 | 5 | -1 | 1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||
c.3305C>T | A1102V![]() | Likely Benign | Benign | 1 | 6-33443857-C-T | -2.440 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -1.27 | Neutral | 0.017 | Benign | 0.028 | Benign | 2.29 | Pathogenic | 0.12 | Tolerated | 3.77 | 5 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
c.3310C>T | P1104S![]() | Likely Benign | Benign | 1 | 6-33443862-C-T | 1 | 6.54e-7 | -2.330 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.30 | Neutral | 0.770 | Possibly Damaging | 0.404 | Benign | 2.77 | Benign | 0.10 | Tolerated | 3.77 | 5 | -1 | 1 | 0.8 | -10.04 | |||||||||||||||||||||||||||
c.3314G>A | R1105Q![]() | Likely Benign | Uncertain | 2 | 6-33443866-G-A | 3 | 1.96e-6 | -3.666 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.21 | Neutral | 0.958 | Probably Damaging | 0.194 | Benign | 2.50 | Benign | 0.16 | Tolerated | 3.77 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
c.3323G>T | S1108I![]() | Uncertain | 1 | 6-33443875-G-T | -3.666 | Likely Benign | 0.292 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -3.73 | Deleterious | 0.971 | Probably Damaging | 0.604 | Possibly Damaging | 2.44 | Pathogenic | 0.10 | Tolerated | 3.77 | 5 | -2 | -1 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||
c.3326T>C | L1109P![]() | Likely Benign | Conflicting | 2 | -5.313 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -0.52 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.65 | Benign | 0.07 | Tolerated | 4.32 | 2 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||
c.3328A>G | S1110G![]() | Likely Benign | Likely Benign | 1 | -4.674 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -2.26 | Neutral | 0.036 | Benign | 0.026 | Benign | 2.19 | Pathogenic | 0.08 | Tolerated | 4.32 | 2 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||
c.3338G>A | G1113D![]() | Likely Benign | Uncertain | 1 | 6-33443890-G-A | -4.638 | Likely Benign | 0.354 | Ambiguous | Likely Benign | 0.061 | Likely Benign | -0.72 | Neutral | 0.029 | Benign | 0.017 | Benign | 2.58 | Benign | 0.34 | Tolerated | 4.32 | 2 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
c.3344T>C | I1115T![]() | Likely Benign | Benign | 9 | 6-33443896-T-C | 20536 | 1.36e-2 | -2.670 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -0.04 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.76 | Benign | 0.23 | Tolerated | 4.32 | 2 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||
c.3355G>A | G1119R![]() | Benign | 1 | 6-33443907-G-A | 64 | 4.23e-5 | -8.489 | Likely Pathogenic | 0.473 | Ambiguous | Likely Benign | 0.303 | Likely Benign | 0.10 | Neutral | 0.969 | Probably Damaging | 0.462 | Possibly Damaging | 4.03 | Benign | 0.10 | Tolerated | 4.32 | 2 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||
c.3364G>A | G1122S![]() | Likely Benign | Benign/Likely benign | 2 | 6-33443916-G-A | 27 | 1.79e-5 | -4.880 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.189 | Likely Benign | -0.08 | Neutral | 0.022 | Benign | 0.006 | Benign | 4.89 | Benign | 0.92 | Tolerated | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
c.3368G>A | G1123D![]() | Uncertain | 1 | 6-33443920-G-A | 2 | 1.33e-6 | -10.321 | Likely Pathogenic | 0.405 | Ambiguous | Likely Benign | 0.360 | Likely Benign | -0.78 | Neutral | 0.500 | Possibly Damaging | 0.157 | Benign | 4.34 | Benign | 0.19 | Tolerated | 3.77 | 5 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||
c.3374G>C | G1125A![]() | Likely Benign | Uncertain | 1 | 6-33443926-G-C | 1 | 6.68e-7 | -6.569 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.232 | Likely Benign | -0.60 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.60 | Benign | 0.11 | Tolerated | 3.77 | 5 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||
c.3379G>A | G1127R![]() | Likely Benign | Uncertain | 1 | 6-33443931-G-A | 2 | 1.34e-6 | -5.949 | Likely Benign | 0.629 | Likely Pathogenic | Likely Benign | 0.341 | Likely Benign | -0.87 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.86 | Benign | 0.12 | Tolerated | 4.32 | 4 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||
c.3379G>C | G1127R![]() | Likely Benign | Conflicting | 2 | 6-33443931-G-C | 16 | 1.07e-5 | -5.949 | Likely Benign | 0.629 | Likely Pathogenic | Likely Benign | 0.341 | Likely Benign | -0.87 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.86 | Benign | 0.12 | Tolerated | 4.32 | 4 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||
c.3380G>C | G1127A![]() | Likely Benign | Conflicting | 4 | 6-33443932-G-C | 4 | 2.68e-6 | -5.949 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -0.43 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.83 | Benign | 1.00 | Tolerated | 4.32 | 4 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||
c.3380G>T | G1127V![]() | Likely Benign | Uncertain | 1 | 6-33443932-G-T | 1 | 6.69e-7 | -6.097 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.230 | Likely Benign | -1.01 | Neutral | 0.004 | Benign | 0.005 | Benign | 4.81 | Benign | 0.17 | Tolerated | 4.32 | 4 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||
c.3394T>C | S1132P![]() | Likely Benign | Conflicting | 3 | 6-33443946-T-C | 1 | 6.74e-7 | -1.423 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.301 | Likely Benign | 0.38 | Neutral | 0.003 | Benign | 0.006 | Benign | 5.40 | Benign | 0.28 | Tolerated | 4.32 | 4 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||
c.3395C>A | S1132Y![]() | Likely Benign | Likely Benign | 1 | -5.894 | Likely Benign | 0.392 | Ambiguous | Likely Benign | 0.401 | Likely Benign | -1.76 | Neutral | 0.500 | Possibly Damaging | 0.208 | Benign | 5.40 | Benign | 0.09 | Tolerated | 4.32 | 4 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||
c.3397A>G | I1133V![]() | Likely Benign | Benign | 1 | 6-33443949-A-G | 22 | 1.48e-5 | -3.362 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.180 | Likely Benign | 0.06 | Neutral | 0.007 | Benign | 0.007 | Benign | 5.47 | Benign | 0.58 | Tolerated | 4.32 | 3 | 4 | 3 | -0.3 | -14.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||
c.3404A>C | K1135T![]() | Likely Benign | Conflicting | 2 | 6-33443956-A-C | 1 | 6.75e-7 | -4.778 | Likely Benign | 0.779 | Likely Pathogenic | Likely Benign | 0.210 | Likely Benign | -0.90 | Neutral | 0.411 | Benign | 0.321 | Benign | 5.46 | Benign | 0.10 | Tolerated | 4.32 | 2 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||
c.3405G>C | K1135N![]() | Likely Benign | Uncertain | 1 | -5.715 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.166 | Likely Benign | -0.97 | Neutral | 0.411 | Benign | 0.321 | Benign | 5.43 | Benign | 0.07 | Tolerated | 4.32 | 2 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||
c.3434A>G | N1145S![]() | Likely Benign | Uncertain | 1 | 6-33444469-A-G | 2 | 1.24e-6 | -0.989 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.308 | Likely Benign | -1.15 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 5.55 | Benign | 0.89 | Tolerated | 4.32 | 4 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||
c.3484C>T | P1162S![]() | Likely Benign | Uncertain | 1 | -2.118 | Likely Benign | 0.913 | Likely Pathogenic | Ambiguous | 0.215 | Likely Benign | -1.93 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.73 | Benign | 0.55 | Tolerated | 3.88 | 3 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
c.3487C>G | H1163D![]() | Uncertain | 1 | -2.107 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.476 | Likely Benign | -2.60 | Deleterious | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 5.44 | Benign | 0.31 | Tolerated | 3.88 | 3 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||
c.3494C>T | S1165L![]() | Likely Benign | Conflicting | 2 | -2.984 | Likely Benign | 0.793 | Likely Pathogenic | Ambiguous | 0.166 | Likely Benign | -2.01 | Neutral | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 2.60 | Benign | 0.33 | Tolerated | 3.88 | 3 | -3 | -2 | 4.6 | 26.08 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||
c.3502A>G | I1168V![]() | Likely Benign | Uncertain | 1 | -3.263 | Likely Benign | 0.524 | Ambiguous | Likely Benign | 0.363 | Likely Benign | -0.14 | Neutral | 0.876 | Possibly Damaging | 0.643 | Possibly Damaging | 5.47 | Benign | 0.84 | Tolerated | 3.88 | 3 | 4 | 3 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||
c.3508A>G | S1170G![]() | Likely Benign | Coiled-coil | Uncertain | 1 | -4.288 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.349 | Likely Benign | -0.81 | Neutral | 0.241 | Benign | 0.229 | Benign | 5.31 | Benign | 0.54 | Tolerated | 4.32 | 4 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
c.3511G>A | A1171T![]() | Likely Benign | Coiled-coil | Uncertain | 1 | -3.658 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.201 | Likely Benign | -0.48 | Neutral | 0.245 | Benign | 0.138 | Benign | 5.45 | Benign | 0.07 | Tolerated | 4.32 | 4 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
c.3529G>A | E1177K![]() | Likely Benign | Coiled-coil | Uncertain | 1 | -3.413 | Likely Benign | 0.944 | Likely Pathogenic | Ambiguous | 0.560 | Likely Pathogenic | -1.75 | Neutral | 0.905 | Possibly Damaging | 0.637 | Possibly Damaging | 5.44 | Benign | 0.11 | Tolerated | 4.32 | 2 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
c.3567G>C | E1189D![]() | Likely Benign | Coiled-coil | Likely Benign | 1 | 6-33444602-G-C | 3 | 1.86e-6 | -3.582 | Likely Benign | 0.461 | Ambiguous | Likely Benign | 0.359 | Likely Benign | -1.42 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 5.30 | Benign | 0.25 | Tolerated | 3.82 | 4 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
c.3572G>A | R1191Q![]() | Likely Benign | Coiled-coil | Uncertain | 2 | 6-33444607-G-A | 9 | 5.58e-6 | -1.069 | Likely Benign | 0.943 | Likely Pathogenic | Ambiguous | 0.343 | Likely Benign | -1.41 | Neutral | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 2.68 | Benign | 0.08 | Tolerated | 3.82 | 4 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||
c.3574C>G | L1192V![]() | Likely Benign | Coiled-coil | Uncertain | 1 | -4.132 | Likely Benign | 0.471 | Ambiguous | Likely Benign | 0.041 | Likely Benign | -0.89 | Neutral | 0.779 | Possibly Damaging | 0.527 | Possibly Damaging | 2.69 | Benign | 0.16 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||
c.3607C>G | H1203D![]() | Likely Benign | Coiled-coil | Uncertain | 1 | -6.729 | Likely Benign | 0.525 | Ambiguous | Likely Benign | 0.403 | Likely Benign | -1.89 | Neutral | 0.473 | Possibly Damaging | 0.265 | Benign | 5.51 | Benign | 0.24 | Tolerated | 3.77 | 5 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
c.3607C>T | H1203Y![]() | Likely Benign | Coiled-coil | Uncertain | 1 | 6-33446599-C-T | 2 | 1.24e-6 | -6.834 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.233 | Likely Benign | -1.52 | Neutral | 0.006 | Benign | 0.011 | Benign | 5.55 | Benign | 0.10 | Tolerated | 3.77 | 5 | 2 | 0 | 1.9 | 26.03 | ||||||||||||||||||||||||||
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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.597C>A | N199K (3D Viewer) ![]() | PH | Uncertain | 1 | -8.198 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | 0.024 | Likely Benign | -0.19 | Likely Benign | 0.1 | 0.03 | Likely Benign | -0.08 | Likely Benign | 0.33 | Likely Benign | -1.48 | Neutral | 0.276 | Benign | 0.083 | Benign | 4.27 | Benign | 0.13 | Tolerated | 3.47 | 9 | 1 | 0 | -0.4 | 14.07 | 207.8 | 21.5 | -0.1 | 1.5 | 0.1 | 0.0 | X | Uncertain | Asn199, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by a positively charged lysine. On the protein surface, both the carboxamide group of Asn199 and the amino group of Lys199 side chains can form hydrogen bonds with the backbone carbonyl groups of residues (e.g., Ala249) at the end of an α helix (res. Ala236-Lys251). However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||||
c.600G>C | L200F (3D Viewer) ![]() | PH | Uncertain | 1 | 6-33435242-G-C | 2 | 1.24e-6 | -7.606 | In-Between | 0.592 | Likely Pathogenic | Likely Benign | 0.094 | Likely Benign | 1.00 | Ambiguous | 0.5 | 1.45 | Ambiguous | 1.23 | Ambiguous | 0.43 | Likely Benign | -1.97 | Neutral | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.02 | Benign | 0.17 | Tolerated | 3.46 | 9 | 2 | 0 | -1.0 | 34.02 | 250.4 | -15.1 | 0.6 | 0.2 | 0.5 | 0.0 | X | Uncertain | Leu200, a hydrophobic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another hydrophobic residue, phenylalanine. Both the phenyl group of Phe200 and the branched iso-butyl hydrocarbon sidechain of Leu200 occupy an inward hydrophobic niche (e.g., Leu246, Val222, Phe231) during the simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||
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.667A>G | T223A (3D Viewer) ![]() | PH | Uncertain | 1 | 6-33435518-A-G | 3 | 1.86e-6 | -7.076 | In-Between | 0.316 | Likely Benign | Likely Benign | 0.574 | Likely Pathogenic | 0.30 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.54 | Ambiguous | 0.74 | Ambiguous | -3.36 | Deleterious | 0.231 | Benign | 0.058 | Benign | 5.74 | Benign | 0.09 | Tolerated | 3.41 | 13 | 1 | 0 | 2.5 | -30.03 | 186.4 | 44.0 | 0.0 | 0.0 | 0.0 | 0.0 | X | X | Uncertain | The introduced residue Ala223 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the hydroxyl group of the Thr223 side chain in the WT protein, the methyl side chain of Ala223 cannot form hydrogen bonds with nearby residues Thr228 and Lys207. Without these hydrogen-bonding interactions at the β sheet surface, the secondary structure element becomes unstable and partially unfolds in 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.694G>A | A232T (3D Viewer) ![]() | PH | Benign | 1 | 6-33435545-G-A | 1 | 6.20e-7 | -7.655 | In-Between | 0.874 | Likely Pathogenic | Ambiguous | 0.469 | Likely Benign | 0.47 | Likely Benign | 0.1 | -0.04 | Likely Benign | 0.22 | Likely Benign | 0.61 | Ambiguous | -1.42 | Neutral | 0.608 | Possibly Damaging | 0.240 | Benign | 5.80 | Benign | 0.09 | Tolerated | 3.40 | 14 | 1 | 0 | -2.5 | 30.03 | 210.8 | -42.0 | 0.5 | 0.1 | 0.4 | 0.5 | X | Uncertain | The hydroxyl group of Thr232, located at the end of an anti-parallel β sheet strand (res. Thr228-Ala232), forms hydrogen bonds with nearby residues Glu217, Cys233, and Cys219 in the variant simulations. These hydrogen-bonding interactions at the β sheet surface contribute to the stability of the secondary structure element and prevent it from unfolding. The new hydrogen bond interactions may be more favorable for structural stability than the steric interactions of the methyl side chain of Ala with the side chains of Gln216 and Cys219 in the WT. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||
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.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.745G>A | A249T (3D Viewer) ![]() | Likely Benign | PH | Uncertain | 1 | -3.564 | Likely Benign | 0.805 | Likely Pathogenic | Ambiguous | 0.487 | Likely Benign | 1.50 | Ambiguous | 0.6 | 1.39 | Ambiguous | 1.45 | Ambiguous | 0.30 | Likely Benign | -0.96 | Neutral | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 5.65 | Benign | 0.40 | Tolerated | 3.39 | 15 | 1 | 0 | -2.5 | 30.03 | 214.5 | -43.3 | 0.0 | 0.0 | 0.5 | 0.2 | X | Potentially Benign | The methyl group of Ala249, located on the surface of an α helix (res. Ala236-Val250) facing an anti-parallel β sheet strand (res. Ile205-Val209), packs against nearby hydrophobic residues such as Leu200, Leu246, and Val250. In the variant simulations, the hydroxyl group of Thr249, which is not suitable for hydrophobic packing, forms a stable hydrogen bond with the backbone carbonyl of Asn245 in the same helix. Although this interaction could theoretically weaken the structural integrity of the α helix, this destabilizing effect is not observed in the variant simulations. | |||||||||||
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.958G>C | V320L (3D Viewer) ![]() | C2 | Uncertain | 1 | 6-33437863-G-C | 6 | 3.72e-6 | -6.207 | Likely Benign | 0.362 | Ambiguous | Likely Benign | 0.096 | Likely Benign | -0.26 | Likely Benign | 0.2 | 1.33 | Ambiguous | 0.54 | Ambiguous | 0.51 | Ambiguous | -1.02 | Neutral | 0.900 | Possibly Damaging | 0.373 | Benign | 1.78 | Pathogenic | 0.92 | Tolerated | 3.38 | 23 | 2 | 1 | -0.4 | 14.03 | 245.8 | -10.2 | 0.3 | 0.9 | 0.1 | 0.3 | X | Potentially Benign | The isopropyl side chain of Val310, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Thr305-Asn315, res. Ala322-Asp330), hydrophobically packs with the side chains of nearby residues (e.g., Leu286, Val350, Pro318). The hydrophobic Leu320 side chain mostly forms the same interactions; hence, the residue swap does not seem to negatively affect the protein structure based on the variant simulations. | |||||||||
c.819G>T | E273D (3D Viewer) ![]() | Likely Benign | C2 | Benign | 1 | 6-33437724-G-T | 2 | 1.24e-6 | -1.811 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.26 | Likely Benign | 0.1 | -0.48 | Likely Benign | -0.11 | Likely Benign | -0.63 | Ambiguous | 1.99 | Neutral | 0.004 | Benign | 0.010 | Benign | 2.00 | Pathogenic | 1.00 | Tolerated | 3.38 | 18 | 3 | 2 | 0.0 | -14.03 | 223.1 | 22.1 | 0.2 | 0.0 | 0.0 | 0.1 | X | Potentially Benign | The negatively charged residue Glu273, located in a β hairpin loop (res. Glu273-Lys278) that connects two anti-parallel β sheet strands, is replaced with another negatively charged residue, aspartate. Because the C2 domain loop faces the membrane surface, the potentially crucial role of the carboxylate group of Glu273 or Asp273 on SynGAP-membrane association cannot be fully explored via solvent-only simulations.As a minor note, the neighboring residue Arg272, which stacks with the indole ring of the Trp362 side chain and directly faces RasGTPase, forms a salt bridge more often with Asp273 than with the non-mutated Glu273 in the simulations. Regardless, due to the similar physicochemical properties of the WT and variant residues at the membrane interface, the residue swap is likely to be well tolerated. | ||||||||
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.865A>G | M289V (3D Viewer) ![]() | Likely Benign | C2 | Benign | 1 | -4.239 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.150 | Likely Benign | 1.09 | Ambiguous | 0.1 | -0.27 | Likely Benign | 0.41 | Likely Benign | 0.24 | Likely Benign | -0.36 | Neutral | 0.136 | Benign | 0.054 | Benign | 1.80 | Pathogenic | 1.00 | Tolerated | 3.38 | 23 | 2 | 1 | 2.3 | -32.06 | 204.2 | 51.0 | 0.0 | 0.0 | 0.2 | 0.0 | X | Potentially Benign | The hydrophobic residue Met289, located in a β hairpin linking two anti-parallel β sheet strands (res. Met289-Arg299, res. Arg272-Leu286), is swapped for another hydrophobic residue, valine. In the variant simulations, the branched hydrocarbon side chain of Val289 packs against the phenol group of the Tyr291 side chain but is unable to form methionine-aromatic interactions. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. However, based on the simulations, the residue swap does not cause adverse effects on the structure. | |||||||||||
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.895C>T | R299C (3D Viewer) ![]() | Likely Pathogenic | C2 | Conflicting | 2 | 6-33437800-C-T | 3 | 1.86e-6 | -6.326 | Likely Benign | 0.572 | Likely Pathogenic | Likely Benign | 0.344 | Likely Benign | 1.85 | Ambiguous | 0.4 | 0.61 | Ambiguous | 1.23 | Ambiguous | 0.76 | Ambiguous | -3.54 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.65 | Pathogenic | 0.06 | Tolerated | 3.39 | 19 | -4 | -3 | 7.0 | -53.05 | 210.7 | 91.3 | 0.1 | 0.0 | 0.0 | 0.2 | X | X | Potentially Pathogenic | The guanidinium group of Arg299, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), forms hydrogen bonds that stabilize the tight turn. In the WT simulations, the Arg299 side chain hydrogen bonds with the loop backbone carbonyl groups (e.g., Ser302, Thr305, Leu274, Gly303), the hydroxyl group of Ser300, and even forms a salt bridge with the carboxylate group of Asp304.In the variant simulations, the thiol group of the Cys299 side chain is unable to form any of these well-coordinated or strong interactions, which could affect the initial formation of the secondary hairpin loop during folding. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Moreover, the positively charged Arg299 side chain faces the polar head group region of the inner leaflet membrane and could directly anchor the C2 domain to the membrane. In short, the residue swap could negatively affect both protein folding and the stability of the SynGAP-membrane association. | |||||||
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.913A>G | T305A (3D Viewer) ![]() | Likely Benign | C2 | Conflicting | 2 | 6-33437818-A-G | 13 | 8.05e-6 | -4.307 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.144 | Likely Benign | 1.30 | Ambiguous | 0.6 | 1.55 | Ambiguous | 1.43 | Ambiguous | 0.77 | Ambiguous | -2.10 | Neutral | 0.939 | Possibly Damaging | 0.645 | Possibly Damaging | 1.76 | Pathogenic | 0.12 | Tolerated | 3.40 | 20 | 1 | 0 | 2.5 | -30.03 | 177.9 | 43.5 | -0.2 | 0.1 | 0.4 | 0.0 | Uncertain | The hydroxyl group of Thr305, located at the beginning of an anti-parallel β strand (res. Thr305-Asn315), hydrogen bonds with the carboxylate groups of Glu270 and Asp304 in the anti-parallel β strand and the adjacent β hairpin loop, respectively. In the variant simulations, the methyl group of the Ala305 side chain cannot hydrogen bond with either of the acidic residues, which could weaken the integrity of the tertiary structure and the β hairpin loop. Indeed, the guanidinium group of Arg299 does not acquire its central hairpin loop position due to the residue swap.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.962G>A | R321H (3D Viewer) ![]() | C2 | Uncertain | 1 | 6-33437867-G-A | 8 | 4.96e-6 | -8.751 | Likely Pathogenic | 0.136 | Likely Benign | Likely Benign | 0.323 | Likely Benign | 0.48 | Likely Benign | 0.1 | -0.36 | Likely Benign | 0.06 | Likely Benign | 0.59 | Ambiguous | -1.43 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.92 | Pathogenic | 0.25 | Tolerated | 3.38 | 23 | 2 | 0 | 1.3 | -19.05 | 218.5 | 86.9 | 1.1 | 0.0 | 0.3 | 0.0 | X | Potentially Benign | The guanidinium group of Arg321, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Thr305-Asn315, res. Ala322-Asp330), faces outward without forming any stable interactions in the WT simulations. Similarly, in the variant simulations, the imidazole ring of His321 also points outward without making any stable intra-protein interactions. Thus, the residue swap does not seem to cause adverse effects on the protein structure based on the simulations. However, β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. | |||||||||
c.970C>T | R324W (3D Viewer) ![]() | Likely Pathogenic | C2 | Uncertain | 1 | 6-33437875-C-T | 2 | 1.24e-6 | -12.906 | Likely Pathogenic | 0.694 | Likely Pathogenic | Likely Benign | 0.481 | Likely Benign | 1.49 | Ambiguous | 0.3 | 0.56 | Ambiguous | 1.03 | Ambiguous | 0.66 | Ambiguous | -3.12 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.82 | Pathogenic | 0.16 | Tolerated | 3.39 | 22 | 2 | -3 | 3.6 | 30.03 | 256.6 | 39.1 | 0.0 | 0.1 | 0.3 | 0.2 | X | Potentially Pathogenic | The guanidinium group of Arg324, located at the end of an anti-parallel β sheet strand (res. Ala322-Asp330), faces outward and frequently forms a salt bridge with the carboxylate group of the Asp288 side chain, which is part of a β strand end (res. Met289-Pro298). In the variant simulations, the indole ring of the Trp324 side chain cannot maintain a similar interaction with the negatively charged carboxylate side chain of Asp288, potentially compromising the folding of the anti-parallel β sheet assembly. However, the residue swap does not appear to negatively impact the protein structure or its integrity based on the simulations. |
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