1-237678063-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_001035.3(RYR2):c.8846G>T(p.Gly2949Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2949D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.70

Publications

1 publications found

Variant links:

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]

RYR2 Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular dysplasia 2
Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
catecholaminergic polymorphic ventricular tachycardia 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RYR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, arrhythmogenic right ventricular cardiomyopathy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.8846G>T	p.Gly2949Val	missense_variant	Exon 61 of 105	ENST00000366574.7	NP_001026.2	Q92736-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR2	ENST00000366574.7 link	c.8846G>T	p.Gly2949Val	missense_variant	Exon 61 of 105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2 link	c.8846G>T	p.Gly2949Val	missense_variant	Exon 61 of 106			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 link	n.8831-2393G>T		intron_variant	Intron 60 of 103	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

244934

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1450066

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721710

African (AFR)

AF:

0.00

AC:

AN:

33318

American (AMR)

AF:

0.00

AC:

AN:

44296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25978

East Asian (EAS)

AF:

0.00

AC:

AN:

39602

South Asian (SAS)

AF:

0.00

AC:

AN:

85320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102566

Other (OTH)

AF:

0.00

AC:

AN:

60000

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:1

Mar 06, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glycine with valine at codon 2949 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular 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

Oct 05, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant does not occur within one of the three regions of the RYR2 gene (N-terminal domain, central domain, or channel region) where other pathogenic variants have been reported to cluster (PMID: 19926015) This variant has not been reported in the literature in individuals with RYR2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 2949 of the RYR2 protein (p.Gly2949Val). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and valine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

D;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.79

T;T

M_CAP

Pathogenic

0.44

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

1.2

L;.

PhyloP100

1.7

PrimateAI

Benign

0.33

PROVEAN

Pathogenic

-5.9

D;.

REVEL

Uncertain

0.59

Sift

Benign

0.040

D;.

Polyphen

0.99

D;.

Vest4

0.27

MutPred

0.29

Loss of disorder (P = 0.0337);.;

MVP

0.67

MPC

0.49

ClinPred

0.89

GERP RS

3.7

Varity_R

0.35

gMVP

0.16

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over