rs34967813

chr1-237678090-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001035.3(RYR2):c.8873A>G(p.Gln2958Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,596,616 control chromosomes in the GnomAD database, including 62,959 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2958K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (4190 hom., cov: 33)
  • Exomes 𝑓: 0.27 (58769 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 7.21

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=0.0015868247).
• BP6: Variant 1-237678090-A-G is Benign according to our data. Variant chr1-237678090-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 36750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237678090-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.8873A>G	p.Gln2958Arg	missense_variant	61/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.8873A>G	p.Gln2958Arg	missense_variant	61/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.8873A>G	p.Gln2958Arg	missense_variant	61/106
RYR2	ENST00000659194.3	c.8873A>G	p.Gln2958Arg	missense_variant	61/105
RYR2	ENST00000609119.2	c.8831-2366A>G		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30640 AN: 152112 Hom.: 4190 Cov.: 33

Gnomad AFR AF: 0.0537

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0760

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.214 AC: 51651 AN: 241208 Hom.: 6938 AF XY: 0.214 AC XY: 27961 AN XY: 130522

Gnomad AFR exome AF: 0.0483

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.000736

Gnomad SAS exome AF: 0.0779

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.307

Gnomad OTH exome AF: 0.243

GnomAD4 exome AF: 0.271 AC: 391396 AN: 1444386 Hom.: 58769 Cov.: 27 AF XY: 0.267 AC XY: 191525 AN XY: 718562

Gnomad4 AFR exome AF: 0.0417

Gnomad4 AMR exome AF: 0.199

Gnomad4 ASJ exome AF: 0.221

Gnomad4 EAS exome AF: 0.000556

Gnomad4 SAS exome AF: 0.0804

Gnomad4 FIN exome AF: 0.246

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.233

GnomAD4 genome AF: 0.201 AC: 30630 AN: 152230 Hom.: 4190 Cov.: 33 AF XY: 0.194 AC XY: 14448 AN XY: 74436

Gnomad4 AFR AF: 0.0536

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0767

Gnomad4 FIN AF: 0.230

Gnomad4 NFE AF: 0.309

Gnomad4 OTH AF: 0.184

Alfa AF: 0.280 Hom.: 12028

Bravo AF: 0.194

TwinsUK AF: 0.311 AC: 1152

ALSPAC AF: 0.319 AC: 1230

ESP6500AA AF: 0.0526 AC: 199

ESP6500EA AF: 0.304 AC: 2499

ExAC AF: 0.211 AC: 25492

Asia WGS AF: 0.0390 AC: 136 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

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	Apr 10, 2012	- -
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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2013	- -

Cardiomyopathy Benign:2

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 26, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Arrhythmogenic right ventricular dysplasia 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 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	0.20
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;T
Eigen	Benign	0.088
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.72	N;.
MutationTaster	Benign	0.0042	P
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Uncertain	0.41
Sift	Benign	0.47	T;.
Polyphen		0.29	B;.
Vest4		0.36
MPC		0.50
ClinPred		0.050	T
GERP RS		5.7
Varity_R		0.34
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs34967813; hg19: chr1-237841390; COSMIC: COSV63683862;