rs565413020
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001035.3(RYR2):āc.1022G>Cā(p.Gly341Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,613,566 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G341G) has been classified as Likely benign.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.1022G>C | p.Gly341Ala | missense_variant | 13/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.1022G>C | p.Gly341Ala | missense_variant | 13/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.1022G>C | p.Gly341Ala | missense_variant | 13/106 | ||||
RYR2 | ENST00000659194.3 | c.1022G>C | p.Gly341Ala | missense_variant | 13/105 | ||||
RYR2 | ENST00000609119.2 | c.1022G>C | p.Gly341Ala | missense_variant, NMD_transcript_variant | 13/104 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152042Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000406 AC: 101AN: 248946Hom.: 0 AF XY: 0.000318 AC XY: 43AN XY: 135042
GnomAD4 exome AF: 0.0000821 AC: 120AN: 1461406Hom.: 1 Cov.: 31 AF XY: 0.0000688 AC XY: 50AN XY: 726990
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74390
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 20, 2018 | The RYR2 c.1022G>C; p.Gly341Ala variant (rs565413020) is reported in a large cohort of individuals referred for unspecified genetic testing, but it has not been described in association with disease (Landstrom 2017). This variant is reported in ClinVar (Variation ID: 412819) and is found in the Latino population with an overall allele frequency of 0.29% (101/34406 alleles) in the Genome Aggregation Database. The glycine at codon 341 is highly conserved, but it occurs as an alanine in several vertebrate species, and computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Gly341Ala variant is uncertain at this time. References: Landstrom AP et al. Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals. Circ Arrhythm Electrophysiol. 2017 Apr;10(4). - |
Catecholaminergic polymorphic ventricular tachycardia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 07, 2019 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 12, 2018 | 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