rs56226196

Positions:

chr1-237783700-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001035.3(RYR2):c.11988C>T(p.Gly3996=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,605,234 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 22 hom., cov: 32)

Exomes 𝑓: 0.015 ( 202 hom. )

Consequence

RYR2
NM_001035.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.343

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=-0.36).

BP6

Variant 1-237783700-C-T is Benign according to our data. Variant chr1-237783700-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 43717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237783700-C-T is described in Lovd as [Benign]. Variant chr1-237783700-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.343 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0131 (1995/152246) while in subpopulation AMR AF= 0.0179 (273/15282). AF 95% confidence interval is 0.0161. There are 22 homozygotes in gnomad4. There are 919 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1995 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.11988C>T	p.Gly3996=	synonymous_variant	90/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.11988C>T	p.Gly3996=	synonymous_variant	90/105	1	NM_001035.3	P1	Q92736-1
RYR2	ENST00000660292.2 linkuse as main transcript	c.12009C>T	p.Gly4003=	synonymous_variant	91/106
RYR2	ENST00000659194.3 linkuse as main transcript	c.11976C>T	p.Gly3992=	synonymous_variant	90/105
RYR2	ENST00000609119.2 linkuse as main transcript	c.*3080C>T		3_prime_UTR_variant, NMD_transcript_variant	89/104	5

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1995

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00968

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.0180

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0174

Gnomad FIN

AF:

0.00255

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0159

Gnomad OTH

AF:

0.0196

GnomAD3 exomes

AF:

0.0117

AC:

2855

AN:

244318

Hom.:

AF XY:

0.0123

AC XY:

1629

AN XY:

132416

show subpopulations

Gnomad AFR exome

AF:

0.00895

Gnomad AMR exome

AF:

0.00907

Gnomad ASJ exome

AF:

0.00405

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0169

Gnomad FIN exome

AF:

0.00308

Gnomad NFE exome

AF:

0.0155

Gnomad OTH exome

AF:

0.0143

GnomAD4 exome

AF:

0.0153

AC:

22170

AN:

1452988

Hom.:

202

Cov.:

AF XY:

0.0153

AC XY:

11069

AN XY:

721268

show subpopulations

Gnomad4 AFR exome

AF:

0.00883

Gnomad4 AMR exome

AF:

0.00920

Gnomad4 ASJ exome

AF:

0.00366

Gnomad4 EAS exome

AF:

0.0000507

Gnomad4 SAS exome

AF:

0.0164

Gnomad4 FIN exome

AF:

0.00357

Gnomad4 NFE exome

AF:

0.0170

Gnomad4 OTH exome

AF:

0.0137

GnomAD4 genome

AF:

0.0131

AC:

1995

AN:

152246

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

919

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00970

Gnomad4 AMR

AF:

0.0179

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0168

Gnomad4 FIN

AF:

0.00255

Gnomad4 NFE

AF:

0.0160

Gnomad4 OTH

AF:

0.0194

Alfa

AF:

0.0135

Hom.:

Bravo

AF:

0.0137

Asia WGS

AF:

0.00924

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 04, 2011	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Catecholaminergic polymorphic ventricular tachycardia 1

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	Invitae	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

- -

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

Jul 28, 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

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

8.0

DANN

Benign

0.58

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