rs56229512

Positions:

chr1-237591776-A-G

Variant summary

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

The NM_001035.3(RYR2):c.4198A>G(p.Ser1400Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,613,390 control chromosomes in the GnomAD database, including 390 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 19 hom., cov: 31)

Exomes 𝑓: 0.022 ( 371 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21

Conservation

PhyloP100: 3.54

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 Benign. Variant got -19 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). GenCC has associacion of gene with 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=0.008523673).

BP6

Variant 1-237591776-A-G is Benign according to our data. Variant chr1-237591776-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 43782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237591776-A-G is described in Lovd as [Benign]. Variant chr1-237591776-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0152 (2310/152266) while in subpopulation NFE AF= 0.0239 (1627/68018). AF 95% confidence interval is 0.023. There are 19 homozygotes in gnomad4. There are 1093 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2310 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.4198A>G	p.Ser1400Gly	missense_variant	32/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.4198A>G	p.Ser1400Gly	missense_variant	32/105	1	NM_001035.3	ENSP00000355533	P1	Q92736-1
RYR2	ENST00000660292.2 linkuse as main transcript	c.4198A>G	p.Ser1400Gly	missense_variant	32/106			ENSP00000499787
RYR2	ENST00000659194.3 linkuse as main transcript	c.4198A>G	p.Ser1400Gly	missense_variant	32/105			ENSP00000499653
RYR2	ENST00000609119.2 linkuse as main transcript	c.4198A>G	p.Ser1400Gly	missense_variant, NMD_transcript_variant	32/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes

AF:

0.0152

AC:

2310

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00391

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.0181

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0126

Gnomad FIN

AF:

0.0170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0239

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0167

AC:

4155

AN:

248504

Hom.:

AF XY:

0.0173

AC XY:

2331

AN XY:

134816

show subpopulations

Gnomad AFR exome

AF:

0.00363

Gnomad AMR exome

AF:

0.00830

Gnomad ASJ exome

AF:

0.0218

Gnomad EAS exome

AF:

0.000224

Gnomad SAS exome

AF:

0.0135

Gnomad FIN exome

AF:

0.0199

Gnomad NFE exome

AF:

0.0234

Gnomad OTH exome

AF:

0.0195

GnomAD4 exome

AF:

0.0222

AC:

32424

AN:

1461124

Hom.:

371

Cov.:

AF XY:

0.0221

AC XY:

16053

AN XY:

726786

show subpopulations

Gnomad4 AFR exome

AF:

0.00290

Gnomad4 AMR exome

AF:

0.00848

Gnomad4 ASJ exome

AF:

0.0193

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.0131

Gnomad4 FIN exome

AF:

0.0221

Gnomad4 NFE exome

AF:

0.0252

Gnomad4 OTH exome

AF:

0.0189

GnomAD4 genome

AF:

0.0152

AC:

2310

AN:

152266

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

1093

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00390

Gnomad4 AMR

AF:

0.0109

Gnomad4 ASJ

AF:

0.0181

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0126

Gnomad4 FIN

AF:

0.0170

Gnomad4 NFE

AF:

0.0239

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0217

Hom.:

Bravo

AF:

0.0139

TwinsUK

AF:

0.0259

AC:

ALSPAC

AF:

0.0262

AC:

101

ESP6500AA

AF:

0.00369

AC:

ESP6500EA

AF:

0.0218

AC:

180

ExAC

AF:

0.0173

AC:

2089

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0222

EpiControl

AF:

0.0222

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 13, 2012	Ser1400Gly in exon 32 of RYR2: This variant is classified as benign based on its high frequency in the general population (dbSNP rs56229512; NHLBI Exome Sequenc ing Project, http://evs.gs.washington.edu/EVS). G=157/A=6507 (EA chromosomes, E SP project) -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 10, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ser1400Gly in the RYR2 gene. This variant is present in the 1000 Genomes browser with an overall allele frequency of 0.96% (http://browser.1000genomes.org/index.htm). This means that it is present in some 2% of individuals. In some ethnic subgroups the allele frequency is as high as 2-3%. This amino acid location is not conserved across paralog proteins RYR1-RYR3, suggesting that it is not important for channel function (https://cardiodb.org/Paralogue_Annotation/residue.php?gene=RYR2&position=1400). Yano et al. (2006) have reported that disease-causing variants in RYR2 cluster within 3 hotspot regions: the N-terminal domain (residues 77-433), the central domain (residues 2246-2534), and the C-terminal domain (residues 3778-4959). This variant falls outside of those 3 hotspots. No variation at nearby residues has been reported in HGMD in association with CPVT or ARVC (HGMD professional version as of January 17, 2014). ClinVar lists it as “Benign”, as submitted by Harvard’s Laboratory for Molecular Medicine. As of 2/2/2015 it has been reported in 14/1897 (0.74%) of African American individuals and 178/4126 (4.31%) of Caucasian individuals in the NHLBI Exome Sequencing Project dataset (for overall prevalence of 3.19%; http://evs.gs.washington.edu/EVS/), and two of the Caucasians with the variant were homozygous for it. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. It is listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) as rs56229512. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not provided

Benign:6

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25925909, 33232181) -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RYR2: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Catecholaminergic polymorphic ventricular tachycardia

Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 15, 2018

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 28, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2015

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.0085

T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.6

N;.

REVEL

Uncertain

0.31

Sift

Benign

0.12

T;.

Polyphen

0.0040

B;.

Vest4

0.13

MPC

0.34

ClinPred

0.011

GERP RS

3.2

Varity_R

0.090

gMVP

0.39

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

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