rs764532025
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_001035.3(RYR2):c.1509C>A(p.Asp503Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000081 in 1,605,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar 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 -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.1509C>A | p.Asp503Glu | missense_variant | Exon 16 of 105 | 1 | NM_001035.3 | ENSP00000355533.2 | ||
RYR2 | ENST00000609119.2 | n.1509C>A | non_coding_transcript_exon_variant | Exon 16 of 104 | 5 | ENSP00000499659.2 | ||||
RYR2 | ENST00000660292.2 | c.1509C>A | p.Asp503Glu | missense_variant | Exon 16 of 106 | ENSP00000499787.2 | ||||
RYR2 | ENST00000659194.3 | c.1509C>A | p.Asp503Glu | missense_variant | Exon 16 of 105 | ENSP00000499653.3 |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151734Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000815 AC: 2AN: 245460Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 133186
GnomAD4 exome AF: 0.00000825 AC: 12AN: 1454116Hom.: 0 Cov.: 39 AF XY: 0.0000111 AC XY: 8AN XY: 723184
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151734Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74046
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
This missense variant replaces aspartic acid with glutamic acid at codon 503 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden arrhythmia death syndrome (PMID: 30670673). This variant has also been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy and in an affected family member (PMID: 32660257). This variant has not been identified 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
This missense variant replaces aspartic acid with glutamic acid at codon 503 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden arrhythmia death syndrome (PMID: 30670673). This variant has also been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy and in an affected family member (PMID: 32660257). This variant has not been identified 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. -
not provided Uncertain:1
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Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 503 of the RYR2 protein (p.Asp503Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with RYR2-related conditions (PMID: 30670673, 32660257). ClinVar contains an entry for this variant (Variation ID: 191479). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR2 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at