1-237784321-G-T
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001035.3(RYR2):c.12609G>T(p.Ala4203=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,613,896 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A4203A) has been classified as Likely benign.
Frequency
Consequence
NM_001035.3 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -21 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.12609G>T | p.Ala4203= | synonymous_variant | 90/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.12609G>T | p.Ala4203= | synonymous_variant | 90/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.12630G>T | p.Ala4210= | synonymous_variant | 91/106 | ||||
RYR2 | ENST00000659194.3 | c.12597G>T | p.Ala4199= | synonymous_variant | 90/105 | ||||
RYR2 | ENST00000609119.2 | c.*3701G>T | 3_prime_UTR_variant, NMD_transcript_variant | 89/104 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000454 AC: 69AN: 152076Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000197 AC: 49AN: 248832Hom.: 0 AF XY: 0.0000963 AC XY: 13AN XY: 134972
GnomAD4 exome AF: 0.0000684 AC: 100AN: 1461702Hom.: 1 Cov.: 33 AF XY: 0.0000454 AC XY: 33AN XY: 727132
GnomAD4 genome AF: 0.000453 AC: 69AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.000417 AC XY: 31AN XY: 74400
ClinVar
Submissions by phenotype
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2012 | p.Ala4203Ala in Exon 90 of RYR2: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence. It has been identified in 0.2% (6/3322) of Afr ican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS;). - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 02, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 12, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Catecholaminergic polymorphic ventricular tachycardia Benign:1
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 22, 2019 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
RYR2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 28, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 14, 2018 | 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