rs760307737
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6
The NM_001035.3(RYR2):c.11197G>A(p.Asp3733Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.11197G>A | p.Asp3733Asn | missense_variant | 81/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.11197G>A | p.Asp3733Asn | missense_variant | 81/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.11185G>A | p.Asp3729Asn | missense_variant | 81/106 | ||||
RYR2 | ENST00000659194.3 | c.11185G>A | p.Asp3729Asn | missense_variant | 81/105 | ||||
RYR2 | ENST00000609119.2 | c.*2289G>A | 3_prime_UTR_variant, NMD_transcript_variant | 80/104 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 152126Hom.: 0 Cov.: 32 FAILED QC
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248642Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134864
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461384Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10AN XY: 726966
GnomAD4 genome ? Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74440
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 09, 2024 | This missense variant replaces aspartic acid with asparagine at codon 3733 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 cardiovascular disorders in the literature. This variant has been identified in 1/248642 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. - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 08, 2021 | This sequence change replaces aspartic acid with asparagine at codon 3733 of the RYR2 protein (p.Asp3733Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs760307737, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 220973). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 2023 | 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