rs684923

Positions:

chr1-237651483-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001035.3(RYR2):c.7806C>T(p.His2602=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,566,190 control chromosomes in the GnomAD database, including 172,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 18079 hom., cov: 33)

Exomes 𝑓: 0.46 ( 154352 hom. )

Consequence

RYR2
NM_001035.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.00800

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.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 1-237651483-C-T is Benign according to our data. Variant chr1-237651483-C-T is described in ClinVar as [Benign]. Clinvar id is 43827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237651483-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.008 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.7806C>T	p.His2602=	synonymous_variant	51/105	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.7806C>T	p.His2602=	synonymous_variant	51/105	1	NM_001035.3	ENSP00000355533	P1	Q92736-1
RYR2	ENST00000660292.2 linkuse as main transcript	c.7806C>T	p.His2602=	synonymous_variant	51/106			ENSP00000499787
RYR2	ENST00000659194.3 linkuse as main transcript	c.7806C>T	p.His2602=	synonymous_variant	51/105			ENSP00000499653
RYR2	ENST00000609119.2 linkuse as main transcript	c.7806C>T	p.His2602=	synonymous_variant, NMD_transcript_variant	51/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes

AF:

0.483

AC:

73360

AN:

151846

Hom.:

18064

Cov.:

show subpopulations

Gnomad AFR

AF:

0.499

Gnomad AMI

AF:

0.407

Gnomad AMR

AF:

0.502

Gnomad ASJ

AF:

0.311

Gnomad EAS

AF:

0.806

Gnomad SAS

AF:

0.535

Gnomad FIN

AF:

0.511

Gnomad MID

AF:

0.439

Gnomad NFE

AF:

0.447

Gnomad OTH

AF:

0.492

GnomAD3 exomes

AF:

0.476

AC:

94744

AN:

198868

Hom.:

23592

AF XY:

0.473

AC XY:

50151

AN XY:

105992

show subpopulations

Gnomad AFR exome

AF:

0.475

Gnomad AMR exome

AF:

0.504

Gnomad ASJ exome

AF:

0.300

Gnomad EAS exome

AF:

0.792

Gnomad SAS exome

AF:

0.499

Gnomad FIN exome

AF:

0.492

Gnomad NFE exome

AF:

0.425

Gnomad OTH exome

AF:

0.450

GnomAD4 exome

AF:

0.461

AC:

651284

AN:

1414224

Hom.:

154352

Cov.:

AF XY:

0.461

AC XY:

323046

AN XY:

700806

show subpopulations

Gnomad4 AFR exome

AF:

0.495

Gnomad4 AMR exome

AF:

0.508

Gnomad4 ASJ exome

AF:

0.305

Gnomad4 EAS exome

AF:

0.805

Gnomad4 SAS exome

AF:

0.505

Gnomad4 FIN exome

AF:

0.484

Gnomad4 NFE exome

AF:

0.444

Gnomad4 OTH exome

AF:

0.475

GnomAD4 genome

AF:

0.483

AC:

73413

AN:

151966

Hom.:

18079

Cov.:

AF XY:

0.488

AC XY:

36275

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.499

Gnomad4 AMR

AF:

0.502

Gnomad4 ASJ

AF:

0.311

Gnomad4 EAS

AF:

0.806

Gnomad4 SAS

AF:

0.533

Gnomad4 FIN

AF:

0.511

Gnomad4 NFE

AF:

0.447

Gnomad4 OTH

AF:

0.495

Alfa

AF:

0.450

Hom.:

31734

Bravo

AF:

0.484

Asia WGS

AF:

0.671

AC:

2330

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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	Sep 16, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2014	- -
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	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Arrhythmogenic right ventricular dysplasia 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Genome-Nilou Lab	Nov 07, 2021	- -

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

- -

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. -

Cardiac arrhythmia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.36

DANN

Benign

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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