SynGap Missense Server

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
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>AR884QLikely BenignUncertain 26-33443203-G-A53.10e-6-3.785Likely Benign0.128Likely BenignLikely Benign0.055Likely Benign-0.42Neutral0.012Benign0.004Benign2.62Benign0.36Tolerated4.324111.0-28.06
c.2669G>AR890HLikely BenignBenign 16-33443221-G-A191.18e-5-3.600Likely Benign0.198Likely BenignLikely Benign0.056Likely Benign-1.29Neutral0.254Benign0.134Benign3.97Benign0.15Tolerated4.324201.3-19.05
c.2669G>CR890PLikely BenignLikely Benign 26-33443221-G-C281.74e-5-1.931Likely Benign0.301Likely BenignLikely Benign0.191Likely Benign-1.21Neutral0.999Probably Damaging0.977Probably Damaging4.02Benign0.28Tolerated4.3240-22.9-59.07
c.2684G>AS895NLikely BenignUncertain 1-6.399Likely Benign0.604Likely PathogenicLikely Benign0.118Likely Benign-0.85Neutral0.991Probably Damaging0.988Probably Damaging2.64Benign0.30Tolerated4.32411-2.727.03
c.2695A>GI899VLikely BenignBenign 16-33443247-A-G63.72e-6-2.569Likely Benign0.074Likely BenignLikely Benign0.040Likely Benign0.09Neutral0.220Benign0.078Benign2.75Benign0.92Tolerated4.32443-0.3-14.03
c.2699C>TT900MLikely BenignConflicting 26-33443251-C-T148.68e-6-3.852Likely Benign0.176Likely BenignLikely Benign0.015Likely Benign-0.81Neutral0.060Benign0.016Benign2.79Benign0.08Tolerated4.324-1-12.630.09
c.2702C>TA901VLikely BenignUncertain 26-33443254-C-T21.24e-6-5.043Likely Benign0.219Likely BenignLikely Benign0.029Likely Benign-1.83Neutral0.106Benign0.009Benign2.64Benign0.17Tolerated3.775002.428.05
c.2710A>GM904VLikely BenignLikely Benign 26-33443262-A-G774.78e-5-2.907Likely Benign0.112Likely BenignLikely Benign0.058Likely Benign-0.33Neutral0.039Benign0.023Benign2.80Benign0.10Tolerated3.775212.3-32.06
c.2711T>CM904TLikely BenignUncertain 1-2.721Likely Benign0.668Likely PathogenicLikely Benign0.042Likely Benign-1.15Neutral0.277Benign0.103Benign2.78Benign0.18Tolerated3.775-1-1-2.6-30.09
c.2714G>AR905HLikely BenignUncertain 16-33443266-G-A84.96e-6-4.182Likely Benign0.457AmbiguousLikely Benign0.192Likely Benign-1.11Neutral1.000Probably Damaging0.991Probably Damaging2.59Benign0.09Tolerated3.775201.3-19.05
c.2729G>CG910ALikely BenignUncertain 16-33443281-G-C16.20e-7-3.587Likely Benign0.361AmbiguousLikely Benign0.209Likely Benign-1.43Neutral0.999Probably Damaging0.999Probably Damaging2.78Benign0.10Tolerated3.775102.214.03
c.2743G>AG915SLikely BenignBenign 16-33443295-G-A95.58e-6-3.557Likely Benign0.083Likely BenignLikely Benign0.050Likely Benign-0.88Neutral0.801Possibly Damaging0.201Benign2.73Benign0.31Tolerated3.77510-0.430.03
c.2765G>AR922QLikely BenignBenign 16-33443317-G-A74.34e-6-3.295Likely Benign0.189Likely BenignLikely Benign0.085Likely Benign-0.27Neutral0.992Probably Damaging0.736Possibly Damaging2.57Benign0.20Tolerated3.775111.0-28.06
c.2768T>AI923NLikely BenignUncertain 1-0.733Likely Benign0.712Likely PathogenicLikely Benign0.108Likely Benign-1.16Neutral0.991Probably Damaging0.793Possibly Damaging2.70Benign0.13Tolerated3.775-2-3-8.00.94
c.2809G>CD937HLikely BenignUncertain 1-0.733Likely Benign0.677Likely PathogenicLikely Benign0.150Likely Benign-1.74Neutral1.000Probably Damaging0.975Probably Damaging2.68Benign0.13Tolerated3.775-110.322.05
c.2812G>AG938RLikely BenignUncertain 1-5.271Likely Benign0.732Likely PathogenicLikely Benign0.141Likely Benign-1.11Neutral0.999Probably Damaging0.985Probably Damaging2.74Benign0.36Tolerated3.775-3-2-4.199.14
c.2818G>AG940SLikely BenignUncertain 16-33443370-G-A16.20e-7-5.451Likely Benign0.084Likely BenignLikely Benign0.135Likely Benign0.45Neutral0.409Benign0.253Benign2.77Benign0.44Tolerated3.77510-0.430.03
c.2818G>CG940RLikely BenignBenign 16-33443370-G-C53.10e-6-6.169Likely Benign0.480AmbiguousLikely Benign0.060Likely Benign0.02Neutral0.922Possibly Damaging0.543Possibly Damaging2.73Benign0.15Tolerated3.775-3-2-4.199.14
c.2835T>AH945QLikely BenignConflicting 26-33443387-T-A31.86e-6-5.248Likely Benign0.091Likely BenignLikely Benign0.343Likely Benign-0.36Neutral0.995Probably Damaging0.939Probably Damaging5.03Benign0.06Tolerated4.32430-0.3-9.01
c.2840G>CG947ALikely BenignLikely Benign 16-33443392-G-C281.73e-5-6.511Likely Benign0.080Likely BenignLikely Benign0.156Likely Benign-0.41Neutral0.224Benign0.131Benign4.97Benign0.10Tolerated4.324102.214.03
c.2852A>GH951RLikely BenignLikely Pathogenic 1-4.964Likely Benign0.125Likely BenignLikely Benign0.185Likely Benign-1.08Neutral0.048Benign0.029Benign5.46Benign0.24Tolerated3.77520-1.319.05
c.2854G>AG952SLikely BenignConflicting 26-33443406-G-A21.24e-6-6.190Likely Benign0.077Likely BenignLikely Benign0.167Likely Benign0.19Neutral0.000Benign0.002Benign3.31Benign0.07Tolerated3.77510-0.430.03
c.2858C>AP953QLikely BenignUncertain 1-6.038Likely Benign0.079Likely BenignLikely Benign0.086Likely Benign-0.78Neutral0.058Benign0.015Benign2.78Benign0.29Tolerated3.7750-1-1.931.01
c.2860C>TP954SLikely BenignLikely Benign 16-33443412-C-T16.20e-7-3.525Likely Benign0.062Likely BenignLikely Benign0.143Likely Benign-0.25Neutral0.954Possibly Damaging0.812Possibly Damaging2.87Benign1.00Tolerated3.7751-10.8-10.04
c.2873A>CH958PLikely BenignBenign 16-33443425-A-C21.24e-6-8.369Likely Pathogenic0.068Likely BenignLikely Benign0.204Likely Benign-0.36Neutral0.925Possibly Damaging0.316Benign4.14Benign0.10Tolerated3.7750-21.6-40.02
c.2881C>TH961YLikely BenignConflicting 26-33443433-C-T31.86e-6-8.051Likely Pathogenic0.157Likely BenignLikely Benign0.102Likely Benign-1.07Neutral0.716Possibly Damaging0.147Benign4.10Benign0.55Tolerated3.775021.926.03
c.2888A>GH963RLikely BenignUncertain 16-33443440-A-G84.96e-6-8.952Likely Pathogenic0.169Likely BenignLikely Benign0.081Likely Benign-1.28Neutral0.001Benign0.003Benign4.15Benign0.24Tolerated3.77520-1.319.05
c.2900G>AR967QLikely BenignBenign/Likely benign 26-33443452-G-A311.92e-5-3.057Likely Benign0.080Likely BenignLikely Benign0.104Likely Benign-0.01Neutral0.994Probably Damaging0.626Possibly Damaging4.21Benign0.36Tolerated4.322111.0-28.06
c.2900G>TR967LLikely BenignUncertain 16-33443452-G-T16.20e-7-3.496Likely Benign0.164Likely BenignLikely Benign0.123Likely Benign-0.99Neutral0.959Probably Damaging0.586Possibly Damaging4.15Benign0.75Tolerated4.322-2-38.3-43.03
c.2909A>GE970GLikely BenignBenign 1-0.167Likely Benign0.139Likely BenignLikely Benign0.139Likely Benign-0.93Neutral0.144Benign0.058Benign4.09Benign0.10Tolerated4.3220-23.1-72.06
c.2914C>GP972ALikely BenignUncertain 16-33443466-C-G16.20e-7-0.167Likely Benign0.045Likely BenignLikely Benign0.046Likely Benign-0.89Neutral0.016Benign0.011Benign4.29Benign0.07Tolerated4.322-113.4-26.04
c.2924C>AT975NLikely BenignUncertain 16-33443476-C-A16.20e-7-4.671Likely Benign0.089Likely BenignLikely Benign0.100Likely Benign-0.58Neutral0.586Possibly Damaging0.302Benign4.13Benign0.07Tolerated4.32200-2.813.00
c.2924C>GT975SLikely BenignUncertain 1-2.743Likely Benign0.068Likely BenignLikely Benign0.109Likely Benign-0.57Neutral0.059Benign0.061Benign4.16Benign0.20Tolerated11-0.1-14.03
c.2924C>TT975ILikely BenignUncertain 16-33443476-C-T63.72e-6-3.912Likely Benign0.164Likely BenignLikely Benign0.068Likely Benign-1.66Neutral0.411Benign0.239Benign4.11Benign0.66Tolerated4.3220-15.212.05
c.2928T>GF976LLikely BenignUncertain 1-2.432Likely Benign0.825Likely PathogenicAmbiguous0.212Likely Benign-0.87Neutral0.264Benign0.102Benign4.20Benign0.53Tolerated4.322201.0-34.02
c.2932C>TP978SLikely BenignUncertain 1-3.913Likely Benign0.151Likely BenignLikely Benign0.085Likely Benign-1.07Neutral0.481Possibly Damaging0.220Benign4.22Benign0.48Tolerated1-10.8-10.04
c.2935T>CF979LLikely BenignUncertain 1-2.341Likely Benign0.870Likely PathogenicAmbiguous0.228Likely Benign-1.00Neutral0.625Possibly Damaging0.430Benign4.22Benign0.73Tolerated4.322201.0-34.02
c.2960A>GD987GLikely PathogenicUncertain 1-4.782Likely Benign0.849Likely PathogenicAmbiguous0.234Likely Benign-2.79Deleterious0.943Possibly Damaging0.808Possibly Damaging2.45Pathogenic0.07Tolerated4.3221-13.1-58.04
c.2998A>GI1000VLikely BenignUncertain 2-4.102Likely Benign0.098Likely BenignLikely Benign0.086Likely Benign-0.20Neutral0.437Benign0.170Benign2.76Benign0.81Tolerated4.32434-0.3-14.03
c.3041G>TG1014VLikely BenignUncertain 1-4.612Likely Benign0.181Likely BenignLikely Benign0.053Likely Benign-2.47Neutral0.818Possibly Damaging0.377Benign2.72Benign0.06Tolerated3.775-1-34.642.08
c.3048C>AD1016ELikely BenignLikely Benign 16-33443600-C-A21.24e-6-3.422Likely Benign0.216Likely BenignLikely Benign0.017Likely Benign-0.37Neutral0.008Benign0.028Benign2.64Benign0.65Tolerated3.775230.014.03
c.3049T>CF1017LLikely BenignBenign 1-2.048Likely Benign0.934Likely PathogenicAmbiguous0.157Likely Benign-2.38Neutral0.798Possibly Damaging0.373Benign2.65Benign0.72Tolerated3.775021.0-34.02
c.3092T>CM1031TLikely BenignUncertain 16-33443644-T-C21.24e-6-1.863Likely Benign0.540AmbiguousLikely Benign0.085Likely Benign-0.24Neutral0.002Benign0.005Benign2.67Benign1.00Tolerated3.775-1-1-2.6-30.09
c.3100C>GP1034ALikely BenignBenign 1-4.174Likely Benign0.178Likely BenignLikely Benign0.060Likely Benign-2.44Neutral0.059Benign0.061Benign2.47Pathogenic0.06Tolerated3.7751-13.4-26.04
c.3103C>AP1035TLikely BenignUncertain 1-4.447Likely Benign0.426AmbiguousLikely Benign0.087Likely Benign-0.96Neutral0.901Possibly Damaging0.537Possibly Damaging2.72Benign0.23Tolerated3.7750-10.93.99
c.3116T>CI1039TLikely BenignUncertain 16-33443668-T-C127.43e-6-2.465Likely Benign0.645Likely PathogenicLikely Benign0.193Likely Benign0.45Neutral0.004Benign0.008Benign2.75Benign0.10Tolerated3.775-10-5.2-12.05
c.3121C>TP1041SLikely BenignConflicting 26-33443673-C-T16.20e-7-4.246Likely Benign0.121Likely BenignLikely Benign0.344Likely Benign-2.72Deleterious0.664Possibly Damaging0.283Benign5.48Benign0.11Tolerated3.7751-10.8-10.04
c.3125A>GQ1042RLikely BenignUncertain 26-33443677-A-G21.24e-6-2.928Likely Benign0.413AmbiguousLikely Benign0.300Likely Benign-1.39Neutral0.586Possibly Damaging0.120Benign5.48Benign0.12Tolerated3.77511-1.028.06
c.3134C>GA1045GLikely BenignBenign/Likely benign 76-33443686-C-G14078.72e-4-3.246Likely Benign0.075Likely BenignLikely Benign0.024Likely Benign-1.21Neutral0.224Benign0.066Benign2.64Benign0.33Tolerated3.77510-2.2-14.0310.1016/j.ajhg.2020.11.011
c.3136C>GP1046ALikely BenignUncertain 16-33443688-C-G16.20e-7-3.246Likely Benign0.048Likely BenignLikely Benign0.041Likely Benign-1.67Neutral0.001Benign0.008Benign2.39Pathogenic0.29Tolerated3.775-113.4-26.04
c.3142G>CG1048RLikely BenignUncertain 1-4.305Likely Benign0.435AmbiguousLikely Benign0.503Likely Pathogenic-0.54Neutral0.919Possibly Damaging0.728Possibly Damaging2.54Benign0.10Tolerated3.775-2-3-4.199.14
c.3151G>TG1051CLikely Pathogenic 1-9.050Likely Pathogenic0.122Likely BenignLikely Benign0.497Likely Benign-0.90Neutral0.971Probably Damaging0.750Possibly Damaging-0.74Pathogenic0.10Tolerated3.775-3-32.946.09
c.3152G>AG1051DBenign 16-33443704-G-A21.24e-6-9.379Likely Pathogenic0.311Likely BenignLikely Benign0.445Likely Benign-0.31Neutral0.761Possibly Damaging0.239Benign-0.74Pathogenic0.39Tolerated3.775-11-3.158.04
c.3154G>AG1052RUncertain 1-9.050Likely Pathogenic0.383AmbiguousLikely Benign0.497Likely Benign-0.41Neutral0.990Probably Damaging0.798Possibly Damaging3.90Benign0.10Tolerated3.775-2-3-4.199.14
c.3160G>AG1054SLikely BenignBenign 16-33443712-G-A321.99e-5-5.294Likely Benign0.075Likely BenignLikely Benign0.160Likely Benign0.21Neutral0.121Benign0.013Benign4.04Benign0.63Tolerated3.77510-0.430.03
c.3161G>AG1054DUncertain 1-10.385Likely Pathogenic0.351AmbiguousLikely Benign0.279Likely Benign-0.26Neutral0.818Possibly Damaging0.266Benign4.07Benign0.37Tolerated3.7751-1-3.158.04
c.3170G>AS1057NLikely BenignUncertain 1-6.386Likely Benign0.117Likely BenignLikely Benign0.218Likely Benign-0.41Neutral0.451Benign0.129Benign5.25Benign0.28Tolerated11-2.727.03
c.3178G>AG1060SLikely BenignUncertain 16-33443730-G-A-4.759Likely Benign0.082Likely BenignLikely Benign0.376Likely Benign-0.08Neutral0.271Benign0.054Benign2.69Benign0.49Tolerated4.32210-0.430.03
c.3179G>TG1060VLikely BenignBenign 16-33443731-G-T16.22e-7-6.966Likely Benign0.103Likely BenignLikely Benign0.369Likely Benign-0.73Neutral0.986Probably Damaging0.728Possibly Damaging2.63Benign0.33Tolerated4.322-1-34.642.08
c.3209G>AR1070KLikely BenignConflicting 2-5.093Likely Benign0.326Likely BenignLikely Benign0.104Likely Benign-1.42Neutral0.049Benign0.048Benign3.86Benign0.09Tolerated3.775320.6-28.01
c.3223C>AQ1075KLikely BenignUncertain 1-5.135Likely Benign0.728Likely PathogenicLikely Benign0.134Likely Benign-0.67Neutral0.963Probably Damaging0.959Probably Damaging2.75Benign1.00Tolerated3.77511-0.40.04
c.3238G>AA1080TLikely BenignConflicting 26-33443790-G-A171.06e-5-3.928Likely Benign0.133Likely BenignLikely Benign0.144Likely Benign-0.19Neutral0.253Benign0.042Benign4.10Benign0.60Tolerated3.77510-2.530.03
c.3238G>TA1080SLikely BenignUncertain 16-33443790-G-T16.26e-7-3.277Likely Benign0.108Likely BenignLikely Benign0.103Likely Benign0.01Neutral0.702Possibly Damaging0.346Benign4.16Benign0.08Tolerated3.77511-2.616.00
c.323A>GK108RLikely BenignUncertain 16-33432188-A-G63.72e-6-2.892Likely Benign0.148Likely BenignLikely Benign0.184Likely Benign0.37Neutral0.993Probably Damaging0.956Probably Damaging4.22Benign1.00Tolerated3.61532-0.628.01
c.3250C>GP1084ALikely BenignUncertain 1-3.928Likely Benign0.066Likely BenignLikely Benign0.114Likely Benign-2.54Deleterious0.649Possibly Damaging0.157Benign4.05Benign0.35Tolerated3.775-113.4-26.04
c.3287A>CE1096ALikely BenignUncertain 1-4.504Likely Benign0.510AmbiguousLikely Benign0.164Likely Benign-1.37Neutral0.626Possibly Damaging0.184Benign2.77Benign0.16Tolerated3.775-105.3-58.04
c.3293G>AS1098NLikely BenignConflicting 26-33443845-G-A63.89e-6-5.120Likely Benign0.156Likely BenignLikely Benign0.063Likely Benign-0.58Neutral0.369Benign0.120Benign2.76Benign0.36Tolerated3.77511-2.727.03
c.3304G>AA1102TLikely BenignUncertain 16-33443856-G-A117.17e-6-3.540Likely Benign0.070Likely BenignLikely Benign0.044Likely Benign-0.30Neutral0.001Benign0.001Benign2.32Pathogenic0.95Tolerated3.77510-2.530.03
c.3304G>CA1102PLikely BenignUncertain 1-5.120Likely Benign0.077Likely BenignLikely Benign0.118Likely Benign-0.97Neutral0.000Benign0.002Benign2.26Pathogenic0.13Tolerated3.775-11-3.426.04
c.3305C>TA1102VLikely BenignBenign 16-33443857-C-T-2.440Likely Benign0.077Likely BenignLikely Benign0.081Likely Benign-1.27Neutral0.017Benign0.028Benign2.29Pathogenic0.12Tolerated3.775002.428.05
c.3310C>TP1104SLikely BenignBenign 16-33443862-C-T16.54e-7-2.330Likely Benign0.073Likely BenignLikely Benign0.088Likely Benign-0.30Neutral0.770Possibly Damaging0.404Benign2.77Benign0.10Tolerated3.775-110.8-10.04
c.3314G>AR1105QLikely BenignUncertain 26-33443866-G-A31.96e-6-3.666Likely Benign0.216Likely BenignLikely Benign0.104Likely Benign-1.21Neutral0.958Probably Damaging0.194Benign2.50Benign0.16Tolerated3.775111.0-28.06
c.3323G>TS1108IUncertain 16-33443875-G-T-3.666Likely Benign0.292Likely BenignLikely Benign0.145Likely Benign-3.73Deleterious0.971Probably Damaging0.604Possibly Damaging2.44Pathogenic0.10Tolerated3.775-2-15.326.08
c.3326T>CL1109PLikely BenignConflicting 2-5.313Likely Benign0.120Likely BenignLikely Benign0.151Likely Benign-0.52Neutral0.002Benign0.003Benign2.65Benign0.07Tolerated4.322-3-3-5.4-16.04
c.3328A>GS1110GLikely BenignLikely Benign 1-4.674Likely Benign0.079Likely BenignLikely Benign0.035Likely Benign-2.26Neutral0.036Benign0.026Benign2.19Pathogenic0.08Tolerated4.322100.4-30.03
c.3338G>AG1113DLikely BenignUncertain 16-33443890-G-A-4.638Likely Benign0.354AmbiguousLikely Benign0.061Likely Benign-0.72Neutral0.029Benign0.017Benign2.58Benign0.34Tolerated4.322-11-3.158.04
c.3344T>CI1115TLikely BenignBenign 96-33443896-T-C205361.36e-2-2.670Likely Benign0.068Likely BenignLikely Benign0.100Likely Benign-0.04Neutral0.000Benign0.001Benign2.76Benign0.23Tolerated4.3220-1-5.2-12.05
c.3355G>AG1119RBenign 16-33443907-G-A644.23e-5-8.489Likely Pathogenic0.473AmbiguousLikely Benign0.303Likely Benign0.10Neutral0.969Probably Damaging0.462Possibly Damaging4.03Benign0.10Tolerated4.322-3-2-4.199.14
c.3364G>AG1122SLikely BenignBenign/Likely benign 26-33443916-G-A271.79e-5-4.880Likely Benign0.072Likely BenignLikely Benign0.189Likely Benign-0.08Neutral0.022Benign0.006Benign4.89Benign0.92Tolerated3.77510-0.430.03
c.3368G>AG1123DUncertain 16-33443920-G-A21.33e-6-10.321Likely Pathogenic0.405AmbiguousLikely Benign0.360Likely Benign-0.78Neutral0.500Possibly Damaging0.157Benign4.34Benign0.19Tolerated3.7751-1-3.158.04
c.3374G>CG1125ALikely BenignUncertain 16-33443926-G-C16.68e-7-6.569Likely Benign0.083Likely BenignLikely Benign0.232Likely Benign-0.60Neutral0.999Probably Damaging0.995Probably Damaging4.60Benign0.11Tolerated3.775102.214.03
c.3379G>AG1127RLikely BenignUncertain 16-33443931-G-A21.34e-6-5.949Likely Benign0.629Likely PathogenicLikely Benign0.341Likely Benign-0.87Neutral0.001Benign0.001Benign4.86Benign0.12Tolerated4.324-2-3-4.199.14
c.3379G>CG1127RLikely BenignConflicting 26-33443931-G-C161.07e-5-5.949Likely Benign0.629Likely PathogenicLikely Benign0.341Likely Benign-0.87Neutral0.001Benign0.001Benign4.86Benign0.12Tolerated4.324-2-3-4.199.14
c.3380G>CG1127ALikely BenignConflicting 46-33443932-G-C42.68e-6-5.949Likely Benign0.080Likely BenignLikely Benign0.164Likely Benign-0.43Neutral0.001Benign0.002Benign4.83Benign1.00Tolerated4.324102.214.03
c.3380G>TG1127VLikely BenignUncertain 16-33443932-G-T16.69e-7-6.097Likely Benign0.094Likely BenignLikely Benign0.230Likely Benign-1.01Neutral0.004Benign0.005Benign4.81Benign0.17Tolerated4.324-1-34.642.08
c.3394T>CS1132PLikely BenignConflicting 36-33443946-T-C16.74e-7-1.423Likely Benign0.144Likely BenignLikely Benign0.301Likely Benign0.38Neutral0.003Benign0.006Benign5.40Benign0.28Tolerated4.3241-1-0.810.04
c.3395C>AS1132YLikely BenignLikely Benign 1-5.894Likely Benign0.392AmbiguousLikely Benign0.401Likely Benign-1.76Neutral0.500Possibly Damaging0.208Benign5.40Benign0.09Tolerated4.324-3-2-0.576.10
c.3397A>GI1133VLikely BenignBenign 16-33443949-A-G221.48e-5-3.362Likely Benign0.067Likely BenignLikely Benign0.180Likely Benign0.06Neutral0.007Benign0.007Benign5.47Benign0.58Tolerated4.32343-0.3-14.0310.1016/j.ajhg.2020.11.011
c.3404A>CK1135TLikely BenignConflicting 26-33443956-A-C16.75e-7-4.778Likely Benign0.779Likely PathogenicLikely Benign0.210Likely Benign-0.90Neutral0.411Benign0.321Benign5.46Benign0.10Tolerated4.3220-13.2-27.07
c.3405G>CK1135NLikely BenignUncertain 1-5.715Likely Benign0.960Likely PathogenicLikely Pathogenic0.166Likely Benign-0.97Neutral0.411Benign0.321Benign5.43Benign0.07Tolerated4.322100.4-14.07
c.3434A>GN1145SLikely BenignUncertain 16-33444469-A-G21.24e-6-0.989Likely Benign0.126Likely BenignLikely Benign0.308Likely Benign-1.15Neutral0.997Probably Damaging0.989Probably Damaging5.55Benign0.89Tolerated4.324112.7-27.03
c.3484C>TP1162SLikely BenignUncertain 1-2.118Likely Benign0.913Likely PathogenicAmbiguous0.215Likely Benign-1.93Neutral1.000Probably Damaging0.999Probably Damaging2.73Benign0.55Tolerated3.8831-10.8-10.04
c.3487C>GH1163DUncertain 1-2.107Likely Benign0.949Likely PathogenicAmbiguous0.476Likely Benign-2.60Deleterious0.991Probably Damaging0.991Probably Damaging5.44Benign0.31Tolerated3.8831-1-0.3-22.05
c.3494C>TS1165LLikely BenignConflicting 2-2.984Likely Benign0.793Likely PathogenicAmbiguous0.166Likely Benign-2.01Neutral0.998Probably Damaging0.992Probably Damaging2.60Benign0.33Tolerated3.883-3-24.626.0810.1016/j.ajhg.2020.11.011
c.3502A>GI1168VLikely BenignUncertain 1-3.263Likely Benign0.524AmbiguousLikely Benign0.363Likely Benign-0.14Neutral0.876Possibly Damaging0.643Possibly Damaging5.47Benign0.84Tolerated3.88343-0.3-14.03
c.3508A>GS1170GLikely BenignCoiled-coilUncertain 1-4.288Likely Benign0.221Likely BenignLikely Benign0.349Likely Benign-0.81Neutral0.241Benign0.229Benign5.31Benign0.54Tolerated4.324100.4-30.03
c.3511G>AA1171TLikely BenignCoiled-coilUncertain 1-3.658Likely Benign0.149Likely BenignLikely Benign0.201Likely Benign-0.48Neutral0.245Benign0.138Benign5.45Benign0.07Tolerated4.32410-2.530.03
c.3529G>AE1177KLikely BenignCoiled-coilUncertain 1-3.413Likely Benign0.944Likely PathogenicAmbiguous0.560Likely Pathogenic-1.75Neutral0.905Possibly Damaging0.637Possibly Damaging5.44Benign0.11Tolerated4.32201-0.4-0.94
c.3567G>CE1189DLikely BenignCoiled-coilLikely Benign 16-33444602-G-C31.86e-6-3.582Likely Benign0.461AmbiguousLikely Benign0.359Likely Benign-1.42Neutral0.992Probably Damaging0.989Probably Damaging5.30Benign0.25Tolerated3.824320.0-14.03
c.3572G>AR1191QLikely BenignCoiled-coilUncertain 26-33444607-G-A95.58e-6-1.069Likely Benign0.943Likely PathogenicAmbiguous0.343Likely Benign-1.41Neutral0.998Probably Damaging0.992Probably Damaging2.68Benign0.08Tolerated3.824111.0-28.06
c.3574C>GL1192VLikely BenignCoiled-coilUncertain 1-4.132Likely Benign0.471AmbiguousLikely Benign0.041Likely Benign-0.89Neutral0.779Possibly Damaging0.527Possibly Damaging2.69Benign0.16Tolerated210.4-14.03
c.3607C>GH1203DLikely BenignCoiled-coilUncertain 1-6.729Likely Benign0.525AmbiguousLikely Benign0.403Likely Benign-1.89Neutral0.473Possibly Damaging0.265Benign5.51Benign0.24Tolerated3.7751-1-0.3-22.05
c.3607C>TH1203YLikely BenignCoiled-coilUncertain 16-33446599-C-T21.24e-6-6.834Likely Benign0.149Likely BenignLikely Benign0.233Likely Benign-1.52Neutral0.006Benign0.011Benign5.55Benign0.10Tolerated3.775201.926.03
c.3631A>GM1211VLikely BenignCoiled-coilBenign 16-33446623-A-G31.86e-6-2.101Likely Benign0.258Likely BenignLikely Benign0.412Likely Benign-0.29Neutral0.932Possibly Damaging0.949Probably Damaging5.43Benign0.72Tolerated3.775122.3-32.06
c.3633G>AM1211ILikely BenignCoiled-coilUncertain 16-33446625-G-A31.86e-6-1.537Likely Benign0.764Likely PathogenicLikely Benign0.298Likely Benign-0.42Neutral0.969Probably Damaging0.968Probably Damaging5.40Benign1.00Tolerated3.775122.6-18.03
c.3638A>CN1213TLikely BenignCoiled-coilConflicting 26-33446630-A-C462.85e-5-5.428Likely Benign0.266Likely BenignLikely Benign0.097Likely Benign-1.08Neutral0.959Probably Damaging0.721Possibly Damaging2.74Benign1.00Tolerated3.775002.8-13.00
c.3638A>GN1213SLikely BenignCoiled-coilBenign 16-33446630-A-G138.05e-6-4.086Likely Benign0.081Likely BenignLikely Benign0.094Likely Benign-0.56Neutral0.906Possibly Damaging0.551Possibly Damaging2.82Benign0.68Tolerated3.775112.7-27.0310.1016/j.ajhg.2020.11.011
c.3662G>AR1221QLikely BenignCoiled-coilConflicting 26-33446654-G-A42.48e-6-5.491Likely Benign0.115Likely BenignLikely Benign0.078Likely Benign-1.46Neutral0.836Possibly Damaging0.153Benign2.56Benign0.12Tolerated3.775111.0-28.06
c.3686A>CQ1229PLikely PathogenicCoiled-coilUncertain 1-10.397Likely Pathogenic0.980Likely PathogenicLikely Pathogenic0.422Likely Benign-3.69Deleterious0.998Probably Damaging0.995Probably Damaging1.75Pathogenic0.12Tolerated3.7750-11.9-31.01
c.3731G>AS1244NLikely PathogenicCoiled-coilUncertain 1-9.008Likely Pathogenic0.751Likely PathogenicLikely Benign0.154Likely Benign-1.87Neutral0.997Probably Damaging0.992Probably Damaging2.10Pathogenic0.15Tolerated3.77511-2.727.03
c.382C>AP128TLikely BenignUncertain 16-33432247-C-A16.20e-7-4.217Likely Benign0.267Likely BenignLikely Benign0.075Likely Benign-0.96Neutral0.952Possibly Damaging0.500Possibly Damaging4.19Benign0.35Tolerated3.744-100.93.99
c.3835G>AA1279TLikely BenignUncertain 26-33447883-G-A21.29e-6-4.871Likely Benign0.071Likely BenignLikely Benign0.178Likely Benign-0.30Neutral0.001Benign0.000Benign2.71Benign0.09Tolerated3.77510-2.530.03
c.3846G>CE1282DLikely BenignUncertain 16-33447894-G-C16.44e-7-3.879Likely Benign0.074Likely BenignLikely Benign0.104Likely Benign-1.26Neutral0.112Benign0.036Benign2.70Benign0.39Tolerated3.775320.0-14.03
c.3848C>TP1283LLikely BenignBenign 16-33447896-C-T322.06e-5-3.740Likely Benign0.093Likely BenignLikely Benign0.047Likely Benign-1.04Neutral0.005Benign0.003Benign2.76Benign0.06Tolerated3.775-3-35.416.04
c.3858A>TE1286DLikely BenignConflicting 46-33447906-A-T1439.22e-5-4.010Likely Benign0.081Likely BenignLikely Benign0.036Likely Benign1.02Neutral0.001Benign0.004Benign2.96Benign1.00Tolerated3.775320.0-14.0310.1016/j.ajhg.2020.11.011
c.3902C>GP1301RLikely BenignUncertain 16-33451776-C-G159.30e-6-4.753Likely Benign0.162Likely BenignLikely Benign0.076Likely Benign-1.13Neutral0.077Benign0.059Benign2.81Benign0.10Tolerated3.7750-2-2.959.07
c.3907G>AG1303SLikely BenignUncertain 1-2.271Likely Benign0.125Likely BenignLikely Benign0.155Likely Benign-0.19Neutral0.649Possibly Damaging0.433Benign2.84Benign0.18Tolerated10-0.430.03
c.3913A>GT1305ALikely BenignConflicting 46-33451787-A-G301.86e-5-2.692Likely Benign0.055Likely BenignLikely Benign0.069Likely Benign1.74Neutral0.000Benign0.001Benign3.24Benign1.00Tolerated3.775102.5-30.03
c.3929C>TT1310MLikely BenignBenign 16-33451803-C-T171.05e-5-4.822Likely Benign0.117Likely BenignLikely Benign0.069Likely Benign2.19Neutral0.021Benign0.005Benign2.98Benign0.93Tolerated3.775-1-12.630.09
c.3932T>CL1311PLikely BenignLikely Benign 16-33451806-T-C16.21e-7-1.831Likely Benign0.079Likely BenignLikely Benign0.123Likely Benign-0.52Neutral0.579Possibly Damaging0.335Benign2.72Benign0.18Tolerated3.775-3-3-5.4-16.04
c.3943T>CW1315RLikely BenignUncertain 10.205Likely Benign0.660Likely PathogenicLikely Benign0.114Likely Benign1.31Neutral0.000Benign0.001Benign4.37Benign0.91Tolerated3.7752-3-3.6-30.03
c.3956C>GA1319GLikely BenignUncertain 26-33451830-C-G-3.927Likely Benign0.084Likely BenignLikely Benign0.128Likely Benign-0.74Neutral0.819Possibly Damaging0.581Possibly Damaging4.07Benign0.06Tolerated3.77510-2.2-14.03
c.3961C>TP1321SLikely BenignUncertain 26-33451835-C-T106.46e-6-4.897Likely Benign0.077Likely BenignLikely Benign0.049Likely Benign0.68Neutral0.028Benign0.004Benign4.27Benign0.71Tolerated3.7751-10.8-10.0410.1016/j.ajhg.2020.11.011
c.3962C>AP1321QLikely BenignBenign 16-33451836-C-A16.58e-7-5.594Likely Benign0.079Likely BenignLikely Benign0.055Likely Benign-0.74Neutral0.659Possibly Damaging0.034Benign4.24Benign0.09Tolerated3.7750-1-1.931.01
c.3964G>CA1322PLikely BenignBenign 16-33451838-G-C-1.153Likely Benign0.063Likely BenignLikely Benign0.090Likely Benign0.03Neutral0.000Benign0.000Benign4.15Benign0.23Tolerated3.7751-1-3.426.04
c.3979C>TP1327SLikely BenignUncertain 16-33451853-C-T-4.744Likely Benign0.131Likely BenignLikely Benign0.092Likely Benign0.28Neutral0.980Probably Damaging0.857Possibly Damaging4.25Benign0.71Tolerated3.7751-10.8-10.04
c.3980C>TP1327LLikely BenignUncertain 16-33451854-C-T21.28e-6-5.264Likely Benign0.242Likely BenignLikely Benign0.142Likely Benign-1.24Neutral0.994Probably Damaging0.908Possibly Damaging4.12Benign0.10Tolerated3.775-3-35.416.04
c.4021G>TA1341SLikely BenignUncertain 16-33451895-G-T-2.867Likely Benign0.078Likely BenignLikely Benign0.099Likely Benign0.80Neutral0.000Benign0.001Benign4.40Benign1.00Tolerated3.77511-2.616.00
c.416G>AS139NLikely BenignUncertain 16-33432713-G-A32.22e-6-4.584Likely Benign0.688Likely PathogenicLikely Benign0.109Likely Benign-0.75Neutral0.149Benign0.047Benign4.14Benign0.24Tolerated3.61511-2.727.03
c.453C>AD151ELikely BenignUncertain 1-5.662Likely Benign0.886Likely PathogenicAmbiguous0.142Likely Benign-2.02Neutral0.984Probably Damaging0.967Probably Damaging3.99Benign0.11Tolerated3.615320.014.03
c.458C>AT153NLikely BenignConflicting 3-0.739Likely Benign0.226Likely BenignLikely Benign0.161Likely Benign0.88Neutral0.888Possibly Damaging0.537Possibly Damaging4.23Benign0.81Tolerated3.61500-2.813.00
c.484C>GR162GLikely BenignUncertain 1-6.985Likely Benign0.664Likely PathogenicLikely Benign0.190Likely Benign-0.73Neutral0.487Possibly Damaging0.272Benign4.09Benign0.78Tolerated3.744-2-34.1-99.14
c.484C>TR162CPathogenic 2-8.157Likely Pathogenic0.787Likely PathogenicAmbiguous0.150Likely Benign-2.05Neutral0.988Probably Damaging0.513Possibly Damaging4.00Benign0.11Tolerated3.744-4-37.0-53.05
c.485G>AR162HUncertain 16-33432782-G-A21.24e-6-9.730Likely Pathogenic0.480AmbiguousLikely Benign0.167Likely Benign-1.13Neutral0.957Probably Damaging0.513Possibly Damaging4.03Benign0.12Tolerated3.744201.3-19.05
c.526A>CS176RLikely BenignUncertain 1-6.492Likely Benign0.987Likely PathogenicLikely Pathogenic0.247Likely Benign0.94Neutral0.718Possibly Damaging0.168Benign4.16Benign0.87Tolerated0-1-3.769.11
c.526A>GS176GUncertain 16-33435168-A-G16.20e-7-7.541In-Between0.360AmbiguousLikely Benign0.066Likely Benign-1.08Neutral0.131Benign0.039Benign4.08Benign0.22Tolerated3.546010.4-30.03
c.597C>AN199K
(3D Viewer)
PHUncertain 1-8.198Likely Pathogenic0.686Likely PathogenicLikely Benign0.024Likely Benign-0.19Likely Benign0.10.03Likely Benign-0.08Likely Benign0.33Likely Benign-1.48Neutral0.276Benign0.083Benign4.27Benign0.13Tolerated3.47910-0.414.07207.821.5-0.11.50.10.0XUncertainAsn199, 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>CL200F
(3D Viewer)
PHUncertain 16-33435242-G-C21.24e-6-7.606In-Between0.592Likely PathogenicLikely Benign0.094Likely Benign1.00Ambiguous0.51.45Ambiguous1.23Ambiguous0.43Likely Benign-1.97Neutral0.997Probably Damaging0.916Probably Damaging4.02Benign0.17Tolerated3.46920-1.034.02250.4-15.10.60.20.50.0XUncertainLeu200, 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>AD201E
(3D Viewer)
Likely BenignPHBenign 1-2.640Likely Benign0.406AmbiguousLikely Benign0.165Likely Benign0.42Likely Benign0.21.99Ambiguous1.21Ambiguous0.23Likely Benign-0.69Neutral0.633Possibly Damaging0.108Benign4.30Benign1.00Tolerated3.469320.014.03258.7-24.80.90.1-0.30.2XUncertainAsp201, 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>GD201E
(3D Viewer)
Likely BenignPHConflicting 26-33435245-T-G201.24e-5-2.640Likely Benign0.406AmbiguousLikely Benign0.165Likely Benign0.42Likely Benign0.21.99Ambiguous1.21Ambiguous0.23Likely Benign-0.69Neutral0.633Possibly Damaging0.108Benign4.30Benign1.00Tolerated3.469320.014.03258.7-24.80.90.1-0.30.2XUncertainAsp201, 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>GT223A
(3D Viewer)
PHUncertain 16-33435518-A-G31.86e-6-7.076In-Between0.316Likely BenignLikely Benign0.574Likely Pathogenic0.30Likely Benign0.10.77Ambiguous0.54Ambiguous0.74Ambiguous-3.36Deleterious0.231Benign0.058Benign5.74Benign0.09Tolerated3.4113102.5-30.03186.444.00.00.00.00.0XXUncertainThe 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>GT224A
(3D Viewer)
PHUncertain 36-33435521-A-G21.24e-6-7.379In-Between0.651Likely PathogenicLikely Benign0.464Likely Benign0.33Likely Benign0.11.05Ambiguous0.69Ambiguous0.91Ambiguous-2.96Deleterious0.243Benign0.079Benign5.57Benign0.57Tolerated3.4113102.5-30.03169.041.4-0.51.1-0.40.0XXUncertainThe 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>AA232T
(3D Viewer)
PHBenign 16-33435545-G-A16.20e-7-7.655In-Between0.874Likely PathogenicAmbiguous0.469Likely Benign0.47Likely Benign0.1-0.04Likely Benign0.22Likely Benign0.61Ambiguous-1.42Neutral0.608Possibly Damaging0.240Benign5.80Benign0.09Tolerated3.401410-2.530.03210.8-42.00.50.10.40.5XUncertainThe 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>CM289TLikely BenignC2Uncertain1-4.668Likely Benign0.238Likely BenignLikely Benign0.222Likely Benign0.73Ambiguous0.10.17Likely Benign0.45Likely Benign-0.01Likely Benign-0.47Neutral0.801Possibly Damaging0.315Benign1.83Pathogenic0.57Tolerated-1-1-2.6-30.09
c.892C>TP298S
(3D Viewer)
Likely BenignC2Benign 16-33437797-C-T53.10e-6-6.342Likely Benign0.144Likely BenignLikely Benign0.189Likely Benign1.38Ambiguous0.21.41Ambiguous1.40Ambiguous0.58Ambiguous-1.20Neutral0.991Probably Damaging0.898Possibly Damaging2.03Pathogenic0.85Tolerated3.3920-110.8-10.04
c.745G>AA249T
(3D Viewer)
Likely BenignPHUncertain 1-3.564Likely Benign0.805Likely PathogenicAmbiguous0.487Likely Benign1.50Ambiguous0.61.39Ambiguous1.45Ambiguous0.30Likely Benign-0.96Neutral0.990Probably Damaging0.815Possibly Damaging5.65Benign0.40Tolerated3.391510-2.530.03214.5-43.30.00.00.50.2XPotentially BenignThe 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>AV320I
(3D Viewer)
Likely BenignC2Uncertain 1-5.220Likely Benign0.111Likely BenignLikely Benign0.027Likely Benign-0.27Likely Benign0.20.66Ambiguous0.20Likely Benign0.01Likely Benign-0.21Neutral0.198Benign0.114Benign1.77Pathogenic0.45Tolerated3.3823340.314.03
c.958G>CV320L
(3D Viewer)
C2Uncertain 16-33437863-G-C63.72e-6-6.207Likely Benign0.362AmbiguousLikely Benign0.096Likely Benign-0.26Likely Benign0.21.33Ambiguous0.54Ambiguous0.51Ambiguous-1.02Neutral0.900Possibly Damaging0.373Benign1.78Pathogenic0.92Tolerated3.382321-0.414.03245.8-10.20.30.90.10.3XPotentially BenignThe 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>TE273D
(3D Viewer)
Likely BenignC2Benign 16-33437724-G-T21.24e-6-1.811Likely Benign0.058Likely BenignLikely Benign0.092Likely Benign0.26Likely Benign0.1-0.48Likely Benign-0.11Likely Benign-0.63Ambiguous1.99Neutral0.004Benign0.010Benign2.00Pathogenic1.00Tolerated3.3818320.0-14.03223.122.10.20.00.00.1XPotentially BenignThe 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>AR324Q
(3D Viewer)
Likely BenignC2Uncertain 36-33437876-G-A31.86e-6-5.001Likely Benign0.173Likely BenignLikely Benign0.307Likely Benign0.56Ambiguous0.10.63Ambiguous0.60Ambiguous1.02Destabilizing-1.17Neutral0.999Probably Damaging0.994Probably Damaging1.92Pathogenic0.41Tolerated3.3922111.0-28.06
c.865A>GM289V
(3D Viewer)
Likely BenignC2Benign 1-4.239Likely Benign0.117Likely BenignLikely Benign0.150Likely Benign1.09Ambiguous0.1-0.27Likely Benign0.41Likely Benign0.24Likely Benign-0.36Neutral0.136Benign0.054Benign1.80Pathogenic1.00Tolerated3.3823212.3-32.06204.251.00.00.00.20.0XPotentially BenignThe 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>GS296A
(3D Viewer)
Likely BenignC2Uncertain 1-6.847Likely Benign0.247Likely BenignLikely Benign0.209Likely Benign0.50Ambiguous0.3-0.26Likely Benign0.12Likely Benign0.35Likely Benign-1.79Neutral0.992Probably Damaging0.987Probably Damaging1.97Pathogenic0.65Tolerated3.4016112.6-16.00182.526.6-0.20.1-0.50.0XPotentially PathogenicThe 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>TR299C
(3D Viewer)
Likely PathogenicC2Conflicting 26-33437800-C-T31.86e-6-6.326Likely Benign0.572Likely PathogenicLikely Benign0.344Likely Benign1.85Ambiguous0.40.61Ambiguous1.23Ambiguous0.76Ambiguous-3.54Deleterious1.000Probably Damaging0.998Probably Damaging1.65Pathogenic0.06Tolerated3.3919-4-37.0-53.05210.791.30.10.00.00.2XXPotentially PathogenicThe 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>AA301T
(3D Viewer)
Likely BenignC2Uncertain 56-33437806-G-A21.24e-6-3.448Likely Benign0.070Likely BenignLikely Benign0.150Likely Benign0.36Likely Benign0.2-0.33Likely Benign0.02Likely Benign0.03Likely Benign-0.25Neutral0.997Probably Damaging0.989Probably Damaging4.15Benign0.22Tolerated4.321410-2.530.03219.8-42.8-0.10.0-0.50.2UncertainThe 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>GT305A
(3D Viewer)
Likely BenignC2Conflicting 26-33437818-A-G138.05e-6-4.307Likely Benign0.078Likely BenignLikely Benign0.144Likely Benign1.30Ambiguous0.61.55Ambiguous1.43Ambiguous0.77Ambiguous-2.10Neutral0.939Possibly Damaging0.645Possibly Damaging1.76Pathogenic0.12Tolerated3.4020102.5-30.03177.943.5-0.20.10.40.0UncertainThe 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>AR321H
(3D Viewer)
C2Uncertain 16-33437867-G-A84.96e-6-8.751Likely Pathogenic0.136Likely BenignLikely Benign0.323Likely Benign0.48Likely Benign0.1-0.36Likely Benign0.06Likely Benign0.59Ambiguous-1.43Neutral1.000Probably Damaging0.998Probably Damaging1.92Pathogenic0.25Tolerated3.3823201.3-19.05218.586.91.10.00.30.0XPotentially BenignThe 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>TR324W
(3D Viewer)
Likely PathogenicC2Uncertain 16-33437875-C-T21.24e-6-12.906Likely Pathogenic0.694Likely PathogenicLikely Benign0.481Likely Benign1.49Ambiguous0.30.56Ambiguous1.03Ambiguous0.66Ambiguous-3.12Deleterious1.000Probably Damaging0.998Probably Damaging1.82Pathogenic0.16Tolerated3.39222-33.630.03256.639.10.00.10.30.2XPotentially PathogenicThe 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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