rs876657988

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_001035.3(RYR2):c.2786G>A(p.Arg929His) variant causes a missense change. The variant allele was found at a frequency of 0.00000518 in 1,545,048 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R929C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 4.13

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 links:

Genome browser will be placed here

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). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. GenCC has associacion of the 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 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.2786G>A	p.Arg929His	missense_variant	24/105	ENST00000366574.7	NP_001026.2	Q92736-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RYR2	ENST00000366574.7 link	c.2786G>A	p.Arg929His	missense_variant	24/105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000609119.2 link	n.2786G>A		non_coding_transcript_exon_variant	24/104	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000660292.2 link	c.2786G>A	p.Arg929His	missense_variant	24/106			ENSP00000499787.2	A0A590UKB7
RYR2	ENST00000659194.3 link	c.2786G>A	p.Arg929His	missense_variant	24/105			ENSP00000499653.3	A0A590UJZ8

Frequencies

GnomAD3 genomes

AF:

0.00000685

AC:

AN:

145996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000500

AC:

AN:

1399052

Hom.:

Cov.:

AF XY:

0.00000289

AC XY:

AN XY:

691780

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000652

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000685

AC:

AN:

145996

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70240

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000149

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 11, 2019

proposed classification - variant undergoing re-assessment, contact laboratory -

Catecholaminergic polymorphic ventricular tachycardia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Mar 05, 2024

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 30, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 929 of the RYR2 protein (p.Arg929His). This variant is present in population databases (no rsID available, gnomAD 0.001%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 26573135, 32516855). ClinVar contains an entry for this variant (Variation ID: 229216). 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 not expected to disrupt RYR2 protein function with a negative 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. -

Catecholaminergic polymorphic ventricular tachycardia 1;C1832931:Arrhythmogenic right ventricular dysplasia 2;C5542154:Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;T

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.66

D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.8

D;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

D;.

Polyphen

0.50

P;.

Vest4

0.38

MVP

0.85

MPC

1.3

ClinPred

1.0

GERP RS

5.5

Varity_R

0.55

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over