rs149514924

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001035.3(RYR2):c.3038G>A(p.Arg1013Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,613,962 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1013W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 10 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:9

Conservation

PhyloP100: 3.35

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 -10 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=0.11755881).

BP6

Variant 1-237548562-G-A is Benign according to our data. Variant chr1-237548562-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161381.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000617 (94/152290) while in subpopulation NFE AF = 0.00107 (73/68022). AF 95% confidence interval is 0.000875. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 94 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.3038G>A	p.Arg1013Gln	missense_variant	Exon 26 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RYR2	ENST00000366574.7 link	c.3038G>A	p.Arg1013Gln	missense_variant	Exon 26 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2 link	c.3038G>A	p.Arg1013Gln	missense_variant	Exon 26 of 106			ENSP00000499393.2
RYR2	ENST00000609119.2 link	n.3038G>A		non_coding_transcript_exon_variant	Exon 26 of 104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes

AF:

0.000618

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000470

AC:

117

AN:

249160

AF XY:

0.000496

show subpopulations

Gnomad AFR exome

AF:

0.000387

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000894

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.00152

AC:

2221

AN:

1461672

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1078

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.000112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00193

AC:

2145

AN:

1111844

Other (OTH)

AF:

0.000911

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

116

231

347

462

578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.000617

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000577

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41558

American (AMR)

AF:

0.000392

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00107

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000951

Hom.:

Bravo

AF:

0.000586

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00133

AC:

ExAC

AF:

0.000455

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Dec 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 30, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26332594, 23396983, 24055113, 24025405, 25637381, 25608792, 23204524, 25351510, 21964171, 19926015, 27538377, 27231019, 27153395, 28404607, 28492532, 25163546, 26899768, 31112425, 30847666) -

Jul 17, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The c.3038G>A (p.Arg1013Gln) in RYR2 gene is a missense change that involves the alteration of a mildly conserved nucleotide and 2/4 in silico tools predict benign outcome. The variant falls within one of the four RyR domains, however no functional studies confirming deleterious effect of the variant on the protein function were published at the time of evaluation. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00045 (55/120324 chrs tested), predominantly in individuals of European ancestry (0.00069; 46/66538 chrs tested). This frequency exceeds the maximal expected allele frequency for a pathogenic variant in this gene (0.0000063). The pathogenicity of the variant was also questioned by recent reports (Olfson, 2015; Paludan-Mller, 2017), where authors indicate that prevalence of the variant in general population is higher than expected for the disorder. The variant was reported in at least one CPVT pt without strong evidence for causality. Lastly, several reputable databases/diagnostic centers classified the variant of interest as VUS. Taking together, based on the prevalence in general population the variant was classified as Benign. -

May 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:2Benign:3

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Oct 11, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely benign. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with catecholaminergic polymorphic ventricular tachycardia 1 (MIM#604772) and left ventricular non-compaction (PMIDs: 12459180, 27646203, 29477366, 31875585, 33500567). Loss of function has been reported for ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (MIM#115000), however dominant negative mechanism has not been excluded (PMID: 33536282). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Penetrance for CPVT is estimated to be 60-70% (PMID: 23549275). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (4) (highest allele count: 31 heterozygotes, 0 homozygotes). (I) 0310 - Variant is present in gnomAD >=0.001 and <0.01 for a dominant condition (2295 heterozygotes, 10 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated RyR domain (DECIPHER). (I) 0710 - Other missense variant(s) comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Arg1013Leu) has been reported once as a VUS (ClinVar). p.(Arg1013Trp) has been reported seven times as a VUS (ClinVar). (I) 0808 - 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported twice as benign, four times as likely benign and eight times as a VUS (ClinVar). It has also been reported as a VUS and benign in individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID:34546463, 38691546), and as VUS and likely benign/benign in patients with conflicting phenotypes (PMID: 38489124, 27231019, 19926015, 21964171). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 18, 2019

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Aug 22, 2023

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Nov 16, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Computational tools suggest impact to protein. MAF 0.07%. Frequ ency too high for gene/disease (RYR2/CPVT). -

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

- -

Cardiomyopathy

Uncertain:1Benign:1

Nov 18, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 05, 2017

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arrhythmogenic right ventricular dysplasia 2

Uncertain:1

Jan 18, 2019

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiovascular phenotype

Benign:1

May 03, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

0.10

BayesDel_addAF

Benign

0.0080

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

T;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.12

T;T

MetaSVM

Uncertain

-0.0092

MutationAssessor

Benign

-0.23

N;.

PhyloP100

3.4

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.6

N;.

REVEL

Pathogenic

0.70

Sift

Benign

0.85

T;.

Polyphen

1.0

D;.

Vest4

0.48

MVP

0.98

MPC

1.2

ClinPred

0.033

GERP RS

5.7

Varity_R

0.19

gMVP

0.49

Mutation Taster

=51/49

polymorphism

(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

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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