rs185237690
Positions:
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001035.3(RYR2):āc.4652A>Gā(p.Asn1551Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,613,046 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00019 ( 0 hom., cov: 33)
Exomes š: 0.00014 ( 1 hom. )
Consequence
RYR2
NM_001035.3 missense
NM_001035.3 missense
Scores
2
6
10
Clinical Significance
Conservation
PhyloP100: 7.57
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 -12 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.016109437).
BP6
Variant 1-237602080-A-G is Benign according to our data. Variant chr1-237602080-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201172.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=2}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00019 (29/152272) while in subpopulation EAS AF= 0.00464 (24/5176). AF 95% confidence interval is 0.0032. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 29 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.4652A>G | p.Asn1551Ser | missense_variant | 35/105 | ENST00000366574.7 | NP_001026.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.4652A>G | p.Asn1551Ser | missense_variant | 35/105 | 1 | NM_001035.3 | ENSP00000355533 | P1 | |
RYR2 | ENST00000660292.2 | c.4652A>G | p.Asn1551Ser | missense_variant | 35/106 | ENSP00000499787 | ||||
RYR2 | ENST00000659194.3 | c.4652A>G | p.Asn1551Ser | missense_variant | 35/105 | ENSP00000499653 | ||||
RYR2 | ENST00000609119.2 | c.4652A>G | p.Asn1551Ser | missense_variant, NMD_transcript_variant | 35/104 | 5 | ENSP00000499659 |
Frequencies
GnomAD3 genomes AF: 0.000191 AC: 29AN: 152154Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000290 AC: 72AN: 248478Hom.: 0 AF XY: 0.000245 AC XY: 33AN XY: 134814
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GnomAD4 exome AF: 0.000141 AC: 206AN: 1460774Hom.: 1 Cov.: 30 AF XY: 0.000142 AC XY: 103AN XY: 726640
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GnomAD4 genome AF: 0.000190 AC: 29AN: 152272Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20AN XY: 74448
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:9
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1Benign:3
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 03, 2024 | - - |
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 20, 2018 | This variant is associated with the following publications: (PMID: 26498160, 23595086, 27452199, 26332594, 27756708, 27538377) - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Arrhythmogenic right ventricular dysplasia 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 15, 2023 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 29, 2018 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 11, 2016 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.
REVEL
Benign
Sift
Benign
T;.
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
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