rs72549415
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_001035.3(RYR2):c.3407C>T(p.Ala1136Val) variant causes a missense change. The variant allele was found at a frequency of 0.00996 in 1,613,936 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. A1136A) has been classified as Likely benign.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -19 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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RYR2 | ENST00000366574.7 | c.3407C>T | p.Ala1136Val | missense_variant | Exon 28 of 105 | 1 | NM_001035.3 | ENSP00000355533.2 | ||
RYR2 | ENST00000609119.2 | n.3407C>T | non_coding_transcript_exon_variant | Exon 28 of 104 | 5 | ENSP00000499659.2 | ||||
RYR2 | ENST00000660292.2 | c.3407C>T | p.Ala1136Val | missense_variant | Exon 28 of 106 | ENSP00000499787.2 | ||||
RYR2 | ENST00000659194.3 | c.3407C>T | p.Ala1136Val | missense_variant | Exon 28 of 105 | ENSP00000499653.3 |
Frequencies
GnomAD3 genomes AF: 0.00716 AC: 1089AN: 152164Hom.: 10 Cov.: 33
GnomAD3 exomes AF: 0.00683 AC: 1701AN: 249104Hom.: 9 AF XY: 0.00653 AC XY: 882AN XY: 135142
GnomAD4 exome AF: 0.0103 AC: 14986AN: 1461654Hom.: 118 Cov.: 31 AF XY: 0.0100 AC XY: 7270AN XY: 727108
GnomAD4 genome AF: 0.00715 AC: 1089AN: 152282Hom.: 10 Cov.: 33 AF XY: 0.00654 AC XY: 487AN XY: 74460
ClinVar
Submissions by phenotype
not provided Benign:8
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RYR2: BS1, BS2 -
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This variant is associated with the following publications: (PMID: 24237251, 24025405, 21315846, 19926015, 19597050, 25569433, 27153395, 26332594, 28404607, 25925909, 30403697) -
not specified Benign:7
Ala1136Val in exon 28 of RYR2: This variant is not expected to have clinical sig nificance because it has been identified in 1.2% (83/6844 chromosomes) of Europe an American chromosomes from a broad population by the NHBLI exome Sequencing Pr oject (http://evs.gs.washington.edu/EVS; dbSNP rs72549415). -
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Cardiomyopathy Benign:3
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Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Catecholaminergic polymorphic ventricular tachycardia Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as 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. -
Arrhythmogenic right ventricular dysplasia 2 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at