chr1-237590681-A-G
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001035.3(RYR2):āc.3849A>Gā(p.Leu1283=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000427 in 1,576,954 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā ā ).
Frequency
Genomes: š 0.0025 ( 3 hom., cov: 31)
Exomes š: 0.00020 ( 1 hom. )
Consequence
RYR2
NM_001035.3 synonymous
NM_001035.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.588
Genes affected
RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.74).
BP6
Variant 1-237590681-A-G is Benign according to our data. Variant chr1-237590681-A-G is described in ClinVar as [Benign]. Clinvar id is 43777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.588 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00253 (385/152288) while in subpopulation AFR AF= 0.00883 (367/41556). AF 95% confidence interval is 0.00809. There are 3 homozygotes in gnomad4. There are 184 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 385 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.3849A>G | p.Leu1283= | synonymous_variant | 31/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.3849A>G | p.Leu1283= | synonymous_variant | 31/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.3849A>G | p.Leu1283= | synonymous_variant | 31/106 | ||||
RYR2 | ENST00000659194.3 | c.3849A>G | p.Leu1283= | synonymous_variant | 31/105 | ||||
RYR2 | ENST00000609119.2 | c.3849A>G | p.Leu1283= | synonymous_variant, NMD_transcript_variant | 31/104 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00252 AC: 384AN: 152170Hom.: 3 Cov.: 31
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GnomAD3 exomes AF: 0.000623 AC: 139AN: 223230Hom.: 0 AF XY: 0.000518 AC XY: 62AN XY: 119726
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GnomAD4 exome AF: 0.000203 AC: 289AN: 1424666Hom.: 1 Cov.: 31 AF XY: 0.000172 AC XY: 121AN XY: 704040
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GnomAD4 genome AF: 0.00253 AC: 385AN: 152288Hom.: 3 Cov.: 31 AF XY: 0.00247 AC XY: 184AN XY: 74464
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ClinVar
Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2012 | p.Leu1283Leu in Exon 31 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 and has been identified in 0.8% (26/3214) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs143603583). - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 29, 2016 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 26, 2016 | Variant summary: The RYR2 c.3849A>G (p.Leu1283Leu) variant causes a synonymous change involving a non-conserved nucleotide with 4/5 splice prediction tools predict no significant impact on normal splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 90/110716 (1/1230), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic RYR2 variant of 1/40000, suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, however, a clinical diagnostic laboratory cites the variant as "benign." Therefore, the variant of interest has been classified as Benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
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 | Jun 18, 2018 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
RYR2-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 15, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 08, 2016 | 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. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at