rs72549415

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001035.3(RYR2):c.3407C>T(p.Ala1136Val) variant causes a missense change. The variant allele was found at a frequency of 0.00996 in 1,613,936 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1136A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0072 ( 10 hom., cov: 33)

Exomes 𝑓: 0.010 ( 118 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23

Conservation

PhyloP100: 4.02

Publications

19 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: Benign. The variant received -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, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, arrhythmogenic right ventricular cardiomyopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.010338664).

BP6

Variant 1-237566759-C-T is Benign according to our data. Variant chr1-237566759-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00715 (1089/152282) while in subpopulation NFE AF = 0.0128 (873/68028). AF 95% confidence interval is 0.0121. There are 10 homozygotes in GnomAd4. There are 487 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1089 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.3407C>T	p.Ala1136Val	missense_variant	Exon 28 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RYR2	ENST00000366574.7 link	c.3407C>T	p.Ala1136Val	missense_variant	Exon 28 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2 link	c.3407C>T	p.Ala1136Val	missense_variant	Exon 28 of 106			ENSP00000499393.2
RYR2	ENST00000609119.2 link	n.3407C>T		non_coding_transcript_exon_variant	Exon 28 of 104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes

AF:

0.00716

AC:

1089

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00400

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00405

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0128

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00683

AC:

1701

AN:

249104

AF XY:

0.00653

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.00338

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00441

Gnomad NFE exome

AF:

0.0123

Gnomad OTH exome

AF:

0.00694

GnomAD4 exome

AF:

0.0103

AC:

14986

AN:

1461654

Hom.:

118

Cov.:

AF XY:

0.0100

AC XY:

7270

AN XY:

727108

show subpopulations

African (AFR)

AF:

0.00158

AC:

AN:

33474

American (AMR)

AF:

0.00246

AC:

110

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00341

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00105

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00588

AC:

314

AN:

53402

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0125

AC:

13860

AN:

1111830

Other (OTH)

AF:

0.00752

AC:

454

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

811

1623

2434

3246

4057

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

512

1024

1536

2048

2560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00715

AC:

1089

AN:

152282

Hom.:

Cov.:

AF XY:

0.00654

AC XY:

487

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

41564

American (AMR)

AF:

0.00399

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00405

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0128

AC:

873

AN:

68028

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

105

157

210

262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00940

Hom.:

Bravo

AF:

0.00643

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00239

AC:

ESP6500EA

AF:

0.0130

AC:

110

ExAC

AF:

0.00705

AC:

853

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00992

EpiControl

AF:

0.0110

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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: 24237251, 24025405, 21315846, 19926015, 19597050, 25569433, 27153395, 26332594, 28404607, 25925909, 30403697) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR2: BS1, BS2 -

not specified

Benign:7

Mar 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala1136Val in exon 28 of RYR2: This variant is not expected to have clinical sig nificance because it has been identified in 1.2% (83/6844 chromosomes) of Europe an American chromosomes from a broad population by the NHBLI exome Sequencing Pr oject (http://evs.gs.washington.edu/EVS; dbSNP rs72549415). -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

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

- -

Apr 08, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1;BP4 -

Jan 09, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:3

Sep 21, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 16, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 06, 2017

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:2

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 09, 2018

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

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 09, 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. -

Arrhythmogenic right ventricular dysplasia 2

Benign:1

Feb 09, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.35

T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.062

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.87

D;D

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.29

N;.

PhyloP100

4.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

1.3

N;.

REVEL

Benign

0.073

Sift

Benign

0.77

T;.

Polyphen

0.0

B;.

Vest4

0.36

MVP

0.25

MPC

0.36

ClinPred

0.0074

GERP RS

5.3

Varity_R

0.044

gMVP

0.81

Mutation Taster

=42/58

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over