rs193922626
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_001035.3(RYR2):βc.4069G>Aβ(p.Asp1357Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,613,802 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 Uncertain significance (β β ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1357H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.4069G>A | p.Asp1357Asn | missense_variant | 31/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.4069G>A | p.Asp1357Asn | missense_variant | 31/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.4069G>A | p.Asp1357Asn | missense_variant | 31/106 | ||||
RYR2 | ENST00000659194.3 | c.4069G>A | p.Asp1357Asn | missense_variant | 31/105 | ||||
RYR2 | ENST00000609119.2 | c.4069G>A | p.Asp1357Asn | missense_variant, NMD_transcript_variant | 31/104 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152040Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248560Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134880
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461644Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727106
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74392
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 9 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Institut fΓΌr Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen | May 01, 2016 | - - |
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 15, 2023 | This missense variant replaces aspartic acid with asparagine at codon 1357 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/248560 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 16, 2019 | This missense variant replaces aspartic acid with asparagine at codon 1357 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/248560 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at