rs72549415

Positions:

• chr1-237566759-C-T

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.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. 13/20 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 4.02

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=0.010338664).
• BP6: Variant 1-237566759-C-T is Benign according to our data. Variant chr1-237566759-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 43770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237566759-C-T is described in Lovd as [Benign]. Variant chr1-237566759-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1089 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.3407C>T	p.Ala1136Val	missense_variant	28/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.3407C>T	p.Ala1136Val	missense_variant	28/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.3407C>T	p.Ala1136Val	missense_variant	28/106
RYR2	ENST00000659194.3	c.3407C>T	p.Ala1136Val	missense_variant	28/105
RYR2	ENST00000609119.2	c.3407C>T	p.Ala1136Val	missense_variant, NMD_transcript_variant	28/104	5

Frequencies

GnomAD3 genomes AF: 0.00716 AC: 1089 AN: 152164 Hom.: 10 Cov.: 33

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

GnomAD3 exomes AF: 0.00683 AC: 1701 AN: 249104 Hom.: 9 AF XY: 0.00653 AC XY: 882 AN XY: 135142

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 SAS exome AF: 0.000980

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.: 31 AF XY: 0.0100 AC XY: 7270 AN XY: 727108

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00341

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00105

Gnomad4 FIN exome AF: 0.00588

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.00752

GnomAD4 genome AF: 0.00715 AC: 1089 AN: 152282 Hom.: 10 Cov.: 33 AF XY: 0.00654 AC XY: 487 AN XY: 74460

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.0101 Hom.: 15

Bravo AF: 0.00643

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00239 AC: 10

ESP6500EA AF: 0.0130 AC: 110

ExAC AF: 0.00705 AC: 853

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00992

EpiControl AF: 0.0110

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	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). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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)	Jan 09, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24237251, 24025405, 21315846, 19926015, 19597050, 25569433, 27153395, 26332594, 28404607, 25925909, 30403697) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	RYR2: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Cardiomyopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Dec 06, 2017	- -

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	Feb 09, 2018	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

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 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. -

Arrhythmogenic right ventricular dysplasia 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 09, 2018

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	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.062
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.29	N;.
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.63	T
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	T
GERP RS		5.3
Varity_R		0.044
gMVP		0.81

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

LitVar

Other links and lift over

dbSNP: rs72549415; hg19: chr1-237730059;