rs202176504
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001035.3(RYR2):āc.3230T>Cā(p.Val1077Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,613,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1077G) has been classified as Uncertain significance.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.3230T>C | p.Val1077Ala | missense_variant | 28/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.3230T>C | p.Val1077Ala | missense_variant | 28/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.3230T>C | p.Val1077Ala | missense_variant | 28/106 | ||||
RYR2 | ENST00000659194.3 | c.3230T>C | p.Val1077Ala | missense_variant | 28/105 | ||||
RYR2 | ENST00000609119.2 | c.3230T>C | p.Val1077Ala | missense_variant, NMD_transcript_variant | 28/104 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000650 AC: 99AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000197 AC: 49AN: 248740Hom.: 0 AF XY: 0.000156 AC XY: 21AN XY: 134916
GnomAD4 exome AF: 0.0000609 AC: 89AN: 1461488Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33AN XY: 727002
GnomAD4 genome ? AF: 0.000643 AC: 98AN: 152326Hom.: 0 Cov.: 33 AF XY: 0.000765 AC XY: 57AN XY: 74490
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 22, 2021 | Variant summary: RYR2 c.3230T>C (p.Val1077Ala) results in a non-conservative amino acid change located in the Ryanodine receptor, SPRY domain 2 of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 248740 control chromosomes. The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is benign. c.3230T>C has been reported in the literature as a VUS in one individual in a cohort of clinical whole exome genetic test referrals (Landstrom_2017). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=3; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 06, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 10, 2016 | Variant classified as Uncertain Significance - Favor Benign. The p.Val1077Ala va riant in RYR2 has been identified in 0.2% (23/9702) of African chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs20 2176504). Computational prediction tools and conservation analysis suggest that the p.Val1077Ala variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Val1077Ala variant is uncertain, these data suggest that i t is more likely to be benign. - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 26, 2018 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 05, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at