rs72549415

Positions:

chr1-237566759-C-T

Variant summary

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

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 (★★).

Frequency

Genomes: 𝑓 0.0072 ( 10 hom., cov: 33)

Exomes 𝑓: 0.010 ( 118 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23

Conservation

PhyloP100: 4.02

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=0.010338664).

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	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.3407C>T	p.Ala1136Val	missense_variant	28/105	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.3407C>T	p.Ala1136Val	missense_variant	28/105	1	NM_001035.3	ENSP00000355533	P1	Q92736-1
RYR2	ENST00000660292.2 linkuse as main transcript	c.3407C>T	p.Ala1136Val	missense_variant	28/106			ENSP00000499787
RYR2	ENST00000659194.3 linkuse as main transcript	c.3407C>T	p.Ala1136Val	missense_variant	28/105			ENSP00000499653
RYR2	ENST00000609119.2 linkuse as main transcript	c.3407C>T	p.Ala1136Val	missense_variant, NMD_transcript_variant	28/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes

AF:

0.00716

AC:

1089

AN:

152164

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00653

AC XY:

882

AN XY:

135142

show subpopulations

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.:

AF XY:

0.0100

AC XY:

7270

AN XY:

727108

show subpopulations

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.:

Cov.:

AF XY:

0.00654

AC XY:

487

AN XY:

74460

show subpopulations

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.:

Bravo

AF:

0.00643

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00239

AC:

ESP6500EA

AF:

0.0130

AC:

110

ExAC

AF:

0.00705

AC:

853

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00992

EpiControl

AF:

0.0110

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 12, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RYR2: BS1, BS2 -

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	Eurofins Ntd Llc (ga)	Jan 09, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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+	-	- -

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	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. -
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

- -

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

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.35

T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.062

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.87

D;D

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.29

N;.

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.63

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

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

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