chr1-237623771-A-G
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4BP6BS1BS2
The NM_001035.3(RYR2):āc.5923A>Gā(p.Met1975Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000306 in 1,600,700 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1975I) 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 -9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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RYR2 | ENST00000366574.7 | c.5923A>G | p.Met1975Val | missense_variant | Exon 39 of 105 | 1 | NM_001035.3 | ENSP00000355533.2 | ||
RYR2 | ENST00000609119.2 | n.5923A>G | non_coding_transcript_exon_variant | Exon 39 of 104 | 5 | ENSP00000499659.2 | ||||
RYR2 | ENST00000660292.2 | c.5923A>G | p.Met1975Val | missense_variant | Exon 39 of 106 | ENSP00000499787.2 | ||||
RYR2 | ENST00000659194.3 | c.5923A>G | p.Met1975Val | missense_variant | Exon 39 of 105 | ENSP00000499653.3 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152010Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000607 AC: 15AN: 247224Hom.: 0 AF XY: 0.0000821 AC XY: 11AN XY: 133998
GnomAD4 exome AF: 0.0000297 AC: 43AN: 1448572Hom.: 0 Cov.: 27 AF XY: 0.0000402 AC XY: 29AN XY: 721398
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152128Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3AN XY: 74374
ClinVar
Submissions by phenotype
not provided Uncertain:4
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Reported in individuals with atrial fibrillation or LVNC as well as in a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death who underwent exome sequencing (PMID: 31539150, 33500567, 23861362); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); This variant is associated with the following publications: (PMID: 32508047, 33500567, 19926015, 31539150, 23861362) -
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not specified Uncertain:1Benign:1
The p.Met1975Val variant in RYR2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 6/66168 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s200318013). Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Met1975Val variant is uncertain. -
Variant summary: RYR2 c.5923A>G (p.Met1975Val) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 247224 control chromosomes. The observed variant frequency is approximately 1.77 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), suggesting that the variant is benign. c.5923A>G has been reported in the literature in individuals affected with atrial fibrilation in which the variant did not segregate with disease (Maltese_2019), in a patient with left ventricular noncompaction without strong evidence for causality (Mazzarotto_2020), and in healthy controls (Luo_2020). These reports do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: two classified as likely benign while four classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Cardiomyopathy Benign:2
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Conduction disorder of the heart Uncertain:1
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Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
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Cardiovascular phenotype Benign:1
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