rs201081663
Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2
The NM_001035.3(RYR2):āc.9923A>Gā(p.Asn3308Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000199 in 1,611,078 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N3308D) has been classified as Uncertain significance.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.9923A>G | p.Asn3308Ser | missense_variant | 69/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.9923A>G | p.Asn3308Ser | missense_variant | 69/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.9923A>G | p.Asn3308Ser | missense_variant | 69/106 | ||||
RYR2 | ENST00000659194.3 | c.9923A>G | p.Asn3308Ser | missense_variant | 69/105 | ||||
RYR2 | ENST00000609119.2 | c.*958A>G | 3_prime_UTR_variant, NMD_transcript_variant | 67/104 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000289 AC: 44AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000392 AC: 96AN: 244926Hom.: 1 AF XY: 0.000429 AC XY: 57AN XY: 132744
GnomAD4 exome AF: 0.000189 AC: 276AN: 1458750Hom.: 1 Cov.: 29 AF XY: 0.000193 AC XY: 140AN XY: 725530
GnomAD4 genome ? AF: 0.000289 AC: 44AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26AN XY: 74494
ClinVar
Submissions by phenotype
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2016 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | May 21, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 22, 2021 | Variant summary: RYR2 c.9923A>G (p.Asn3308Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 244926 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 11.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is benign. c.9923A>G has been reported in the literature, without strong evidence for causality (Landstrom_2017, Marjamaa_2009, Medeiros-Domingo_2009). The variant was reported experimentally to have open probabilities similar to the wild type channels in vitro (Marjamaa_2008). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | Apr 17, 2014 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 18, 2018 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2020 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1;C1832931:Arrhythmogenic right ventricular dysplasia 2;C5542154:Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 12, 2021 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 29, 2019 | 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