rs1314129285
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2
The NM_001035.3(RYR2):āc.7550A>Gā(p.Asn2517Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 33)
Exomes š: 0.0000096 ( 0 hom. )
Consequence
RYR2
NM_001035.3 missense
NM_001035.3 missense
Scores
11
5
2
Clinical Significance
Conservation
PhyloP100: 9.31
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 -1 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, RYR2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.898
BS2
?
High AC in GnomAdExome4 at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.7550A>G | p.Asn2517Ser | missense_variant | 50/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.7550A>G | p.Asn2517Ser | missense_variant | 50/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.7550A>G | p.Asn2517Ser | missense_variant | 50/106 | ||||
RYR2 | ENST00000659194.3 | c.7550A>G | p.Asn2517Ser | missense_variant | 50/105 | ||||
RYR2 | ENST00000609119.2 | c.7550A>G | p.Asn2517Ser | missense_variant, NMD_transcript_variant | 50/104 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152130Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461688Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727126
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152130Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74308
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 02, 2023 | This missense variant replaces asparagine with serine at codon 2517 of 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has not been identified 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. - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2517 of the RYR2 protein (p.Asn2517Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 463637). 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 with a positive predictive value of 95%. 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 18, 2023 | The p.N2517S variant (also known as c.7550A>G), located in coding exon 50 of the RYR2 gene, results from an A to G substitution at nucleotide position 7550. The asparagine at codon 2517 is replaced by serine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Polyphen
D;.
Vest4
MutPred
Loss of stability (P = 0.2826);.;
MVP
MPC
ClinPred
D
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