rs561321743
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The ENST00000366574.7(RYR2):āc.2630A>Cā(p.His877Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,612,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H877Y) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000366574.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.2630A>C | p.His877Pro | missense_variant | 23/105 | ENST00000366574.7 | NP_001026.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.2630A>C | p.His877Pro | missense_variant | 23/105 | 1 | NM_001035.3 | ENSP00000355533 | P1 | |
RYR2 | ENST00000660292.2 | c.2630A>C | p.His877Pro | missense_variant | 23/106 | ENSP00000499787 | ||||
RYR2 | ENST00000659194.3 | c.2630A>C | p.His877Pro | missense_variant | 23/105 | ENSP00000499653 | ||||
RYR2 | ENST00000609119.2 | c.2630A>C | p.His877Pro | missense_variant, NMD_transcript_variant | 23/104 | 5 | ENSP00000499659 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152152Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000799 AC: 198AN: 247924Hom.: 0 AF XY: 0.000573 AC XY: 77AN XY: 134438
GnomAD4 exome AF: 0.000153 AC: 223AN: 1460598Hom.: 0 Cov.: 30 AF XY: 0.000125 AC XY: 91AN XY: 726448
GnomAD4 genome AF: 0.000105 AC: 16AN: 152270Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74476
ClinVar
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 05, 2018 | Variant summary: RYR2 c.2630A>C (p.His877Pro) results in a non-conservative amino acid change located in the Ryanodine receptor Ryr domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00071 in 276002 control chromosomes, predominantly within the Latino subpopulation at a frequency of 0.0055 in the gnomAD database. The observed variant frequency within Latino control individuals is approximately 92-fold above the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.2630A>C in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 20, 2015 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 01, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 13, 2020 | This variant is associated with the following publications: (PMID: 28404607) - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | Oct 07, 2014 | - - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 03, 2018 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2023 | - - |
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Dec 24, 2018 | - - |
RYR2-related disorder Benign:1
Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 08, 2024 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 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