rs75206601

Positions:

chr1-237809023-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.14421C>T(p.Asp4807=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00309 in 1,612,892 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 67 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 65 hom. )

Consequence

RYR2
NM_001035.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.607

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=-0.3).

BP6

Variant 1-237809023-C-T is Benign according to our data. Variant chr1-237809023-C-T is described in ClinVar as [Benign]. Clinvar id is 43742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237809023-C-T is described in Lovd as [Benign]. Variant chr1-237809023-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.607 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.054 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.14421C>T	p.Asp4807=	synonymous_variant	100/105	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.14421C>T	p.Asp4807=	synonymous_variant	100/105	1	NM_001035.3	ENSP00000355533	P1	Q92736-1

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2442

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0559

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00596

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00765

GnomAD3 exomes

AF:

0.00414

AC:

1031

AN:

248748

Hom.:

AF XY:

0.00314

AC XY:

424

AN XY:

134952

show subpopulations

Gnomad AFR exome

AF:

0.0558

Gnomad AMR exome

AF:

0.00262

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000443

Gnomad OTH exome

AF:

0.00266

GnomAD4 exome

AF:

0.00174

AC:

2542

AN:

1460592

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

1061

AN XY:

726632

show subpopulations

Gnomad4 AFR exome

AF:

0.0583

Gnomad4 AMR exome

AF:

0.00300

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000157

Gnomad4 OTH exome

AF:

0.00414

GnomAD4 genome

AF:

0.0161

AC:

2449

AN:

152300

Hom.:

Cov.:

AF XY:

0.0156

AC XY:

1162

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0559

Gnomad4 AMR

AF:

0.00589

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.00864

Hom.:

Bravo

AF:

0.0189

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2012	Asp4807Asp in exon 100 of RYR2: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 6.8% (8/118) of ch romosomes from a broad, though clinically and racially unspecified population (d bSNP rs75206601). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 03, 2015	- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

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

- -

Arrhythmogenic right ventricular dysplasia 2

Benign:1

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. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 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

BayesDel_noAF

Benign

-0.30

CADD

Benign

0.17

DANN

Benign

0.49

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