rs201211033
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_001035.3(RYR2):c.556G>A(p.Val186Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,613,312 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
RYR2
NM_001035.3 missense
NM_001035.3 missense
Scores
5
10
3
Clinical Significance
Conservation
PhyloP100: 4.77
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 Likely_benign. Variant got -3 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR2. . Gene score misZ 5.7809 (greater than the threshold 3.09). Trascript score misZ 6.4158 (greater than threshold 3.09). GenCC has associacion of gene with hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.
BS2
High AC in GnomAdExome4 at 19 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RYR2 | NM_001035.3 | c.556G>A | p.Val186Met | missense_variant | 8/105 | ENST00000366574.7 | NP_001026.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR2 | ENST00000366574.7 | c.556G>A | p.Val186Met | missense_variant | 8/105 | 1 | NM_001035.3 | ENSP00000355533 | P1 | |
| RYR2 | ENST00000660292.2 | c.556G>A | p.Val186Met | missense_variant | 8/106 | ENSP00000499787 | ||||
| RYR2 | ENST00000659194.3 | c.556G>A | p.Val186Met | missense_variant | 8/105 | ENSP00000499653 | ||||
| RYR2 | ENST00000609119.2 | c.556G>A | p.Val186Met | missense_variant, NMD_transcript_variant | 8/104 | 5 | ENSP00000499659 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152168Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000241 AC: 6AN: 248524Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134948
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GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461144Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10AN XY: 726874
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GnomAD4 genome 0.0000197 AC: 3AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74340
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Polymorphic ventricular tachycardia Uncertain:2
| Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Apr 05, 2018 | - - |
| Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 08, 2023 | This variant is located in the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Crystal structure study has suggested that this variant may cause a change in the surface of the protein (PMID: 19913485). This variant has been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 16818210). This variant has also been identified in 6/248524 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. - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 28, 2023 | This variant is located in the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Crystal structure study has suggested that this variant may cause a change in the surface of the protein (PMID: 19913485). This variant has been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 16818210). This variant has also been identified in 6/248524 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. - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 07, 2021 | Reported in one patient referred for catecholaminergic polymorphic ventricular tachycardia genetic testing (Tester et al., 2006); however, detailed clinical information was not provided; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 161382; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009); This variant is associated with the following publications: (PMID: 32899693, 25637381, 19913485, 24025405, 27538377, 16818210) - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 11, 2022 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 186 of the RYR2 protein (p.Val186Met). This variant is present in population databases (rs201211033, gnomAD 0.007%). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 16818210). ClinVar contains an entry for this variant (Variation ID: 161382). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. 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 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 02, 2024 | The p.V186M variant (also known as c.556G>A), located in coding exon 8 of the RYR2 gene, results from a G to A substitution at nucleotide position 556. The valine at codon 186 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in an individual reported to have catecholaminergic polymorphic ventricular tachycardia and possible left ventricular non-compaction (Tester DJ et al. Heart Rhythm, 2006 Jul;3:800-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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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