rs942040362
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2
The NM_001035.3(RYR2):c.11116G>A(p.Asp3706Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000237 in 1,561,314 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. D3706Y) 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 -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.11116G>A | p.Asp3706Asn | missense_variant | 80/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.11116G>A | p.Asp3706Asn | missense_variant | 80/105 | 1 | NM_001035.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000166 AC: 25AN: 150606Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000536 AC: 1AN: 186494Hom.: 0 AF XY: 0.0000101 AC XY: 1AN XY: 99030
GnomAD4 exome AF: 0.00000851 AC: 12AN: 1410708Hom.: 0 Cov.: 29 AF XY: 0.0000115 AC XY: 8AN XY: 697960
GnomAD4 genome ? AF: 0.000166 AC: 25AN: 150606Hom.: 0 Cov.: 32 AF XY: 0.000150 AC XY: 11AN XY: 73346
ClinVar
Submissions by phenotype
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 variant is located in 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual from a cohort of clinical whole-exome genetic test referrals (PMID: 28404607). This variant has been identified in 2/217498 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 | Mar 13, 2023 | This missense variant replaces aspartic acid with asparagine at codon 3706 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 2/217498 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2021 | Reported as an incidental finding in a cohort of individuals referred for whole exome sequencing; however, specific clinical information about the individual(s) harboring this variant was not provided (Landstrom et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#450136; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter 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 (Medeiros-Domingo et al., 2009); This variant is associated with the following publications: (PMID: 28404607) - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at