rs56229512

chr1-237591776-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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. 11/19 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. S1400S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (19 hom., cov: 31)
  • Exomes 𝑓: 0.022 (371 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 3.54

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR2
• 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. This position pass quality control queck.
• BS2: High AC in GnomAd at 2310 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.4198A>G	p.Ser1400Gly	missense_variant	32/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.4198A>G	p.Ser1400Gly	missense_variant	32/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.4198A>G	p.Ser1400Gly	missense_variant	32/106
RYR2	ENST00000659194.3	c.4198A>G	p.Ser1400Gly	missense_variant	32/105
RYR2	ENST00000609119.2	c.4198A>G	p.Ser1400Gly	missense_variant, NMD_transcript_variant	32/104	5

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2310 AN: 152148 Hom.: 19 Cov.: 31

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.: 37 AF XY: 0.0173 AC XY: 2331 AN XY: 134816

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.: 30 AF XY: 0.0221 AC XY: 16053 AN XY: 726786

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.: 19 Cov.: 31 AF XY: 0.0147 AC XY: 1093 AN XY: 74456

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.: 59

Bravo AF: 0.0139

TwinsUK AF: 0.0259 AC: 96

ALSPAC AF: 0.0262 AC: 101

ESP6500AA AF: 0.00369 AC: 14

ESP6500EA AF: 0.0218 AC: 180

ExAC AF: 0.0173 AC: 2089

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0222

EpiControl AF: 0.0222

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RYR2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25925909, 33232181) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
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	Invitae	Feb 01, 2024	- -
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. -

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

- -

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0085	T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.60	T
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	T
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

Other links and lift over

dbSNP: rs56229512; hg19: chr1-237755076;