rs41315858

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001035.3(RYR2):c.5654G>A(p.Gly1885Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,609,734 control chromosomes in the GnomAD database, including 537 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1885A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 25 hom., cov: 32)

Exomes 𝑓: 0.024 ( 512 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:21

Conservation

PhyloP100: 0.388

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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, 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=0.0018713474).

BP6

Variant 1-237614782-G-A is Benign according to our data. Variant chr1-237614782-G-A is described in ClinVar as [Benign]. Clinvar id is 36746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237614782-G-A is described in Lovd as [Pathogenic]. Variant chr1-237614782-G-A is described in Lovd as [Benign]. Variant chr1-237614782-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0171 (2599/152334) while in subpopulation NFE AF= 0.0282 (1921/68024). AF 95% confidence interval is 0.0272. There are 25 homozygotes in gnomad4. There are 1194 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2599 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.5654G>A	p.Gly1885Glu	missense_variant	Exon 37 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.5654G>A	p.Gly1885Glu	missense_variant	Exon 37 of 105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000609119.2 link	n.5654G>A		non_coding_transcript_exon_variant	Exon 37 of 104	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000660292.2 link	c.5654G>A	p.Gly1885Glu	missense_variant	Exon 37 of 106			ENSP00000499787.2	A0A590UKB7
RYR2	ENST00000659194.3 link	c.5654G>A	p.Gly1885Glu	missense_variant	Exon 37 of 105			ENSP00000499653.3	A0A590UJZ8

Frequencies

GnomAD3 genomes

AF:

0.0171

AC:

2600

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00533

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0161

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0283

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.0156

AC:

3828

AN:

245448

Hom.:

AF XY:

0.0154

AC XY:

2057

AN XY:

133354

show subpopulations

Gnomad AFR exome

AF:

0.00431

Gnomad AMR exome

AF:

0.00874

Gnomad ASJ exome

AF:

0.00830

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00152

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.0263

Gnomad OTH exome

AF:

0.0180

GnomAD4 exome

AF:

0.0239

AC:

34852

AN:

1457400

Hom.:

512

Cov.:

AF XY:

0.0232

AC XY:

16835

AN XY:

724356

show subpopulations

Gnomad4 AFR exome

AF:

0.00342

Gnomad4 AMR exome

AF:

0.00888

Gnomad4 ASJ exome

AF:

0.00721

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00173

Gnomad4 FIN exome

AF:

0.0149

Gnomad4 NFE exome

AF:

0.0289

Gnomad4 OTH exome

AF:

0.0193

GnomAD4 genome

AF:

0.0171

AC:

2599

AN:

152334

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1194

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00531

Gnomad4 AMR

AF:

0.0161

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.0140

Gnomad4 NFE

AF:

0.0282

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.0229

Hom.:

Bravo

AF:

0.0161

TwinsUK

AF:

0.0337

AC:

125

ALSPAC

AF:

0.0306

AC:

118

ESP6500AA

AF:

0.00526

AC:

ESP6500EA

AF:

0.0234

AC:

195

ExAC

AF:

0.0149

AC:

1803

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0264

EpiControl

AF:

0.0256

ClinVar

Significance: Benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 28, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 10, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Allele frequency = 2.4% (n=160 alleles), EA cohort, NHLBI ESP. -

Nov 21, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:6

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30403697, 25925909, 28798025, 28404607, 27153395, 21315846, 19926015, 24025405, 24237251, 18326664) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR2: BP4, BS1, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Catecholaminergic polymorphic ventricular tachycardia

Benign:1

Nov 20, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Nov 10, 2014

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy

Benign:1

Mar 15, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 2

Benign:1

May 11, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype

Benign:1

Mar 25, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.53

CADD

Benign

4.4

DANN

Benign

0.50

DEOGEN2

Benign

0.33

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.81

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.60

N;.

PrimateAI

Benign

0.32

PROVEAN

Benign

0.55

N;.

REVEL

Benign

0.090

Sift

Benign

0.89

T;.

Polyphen

0.0

B;.

Vest4

0.067

MPC

0.47

ClinPred

0.0052

GERP RS

-2.4

Varity_R

0.049

gMVP

0.11

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