rs3841805

Positions:

chr1-237602011-TA-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001035.3(RYR2):c.4597-11del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,605,380 control chromosomes in the GnomAD database, including 90 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 29 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 61 hom. )

Consequence

RYR2
NM_001035.3 splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.487

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 -16 ACMG points.

BP6

Variant 1-237602011-TA-T is Benign according to our data. Variant chr1-237602011-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 43786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237602011-TA-T is described in Lovd as [Benign]. Variant chr1-237602011-TA-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.011 (1670/152308) while in subpopulation EAS AF= 0.0357 (185/5184). AF 95% confidence interval is 0.0315. There are 29 homozygotes in gnomad4. There are 775 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1670 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.4597-11del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.4597-11del	splice_polypyrimidine_tract_variant, intron_variant	1	NM_001035.3	ENSP00000355533	P1	Q92736-1
RYR2	ENST00000659194.3 linkuse as main transcript	c.4597-11del	splice_polypyrimidine_tract_variant, intron_variant			ENSP00000499653
RYR2	ENST00000660292.2 linkuse as main transcript	c.4597-11del	splice_polypyrimidine_tract_variant, intron_variant			ENSP00000499787
RYR2	ENST00000609119.2 linkuse as main transcript	c.4597-11del	splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant	5		ENSP00000499659

Frequencies

GnomAD3 genomes

AF:

0.0110

AC:

1674

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0360

Gnomad SAS

AF:

0.00289

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00957

GnomAD3 exomes

AF:

0.00532

AC:

1304

AN:

244908

Hom.:

AF XY:

0.00432

AC XY:

573

AN XY:

132786

show subpopulations

Gnomad AFR exome

AF:

0.0371

Gnomad AMR exome

AF:

0.00238

Gnomad ASJ exome

AF:

0.000202

Gnomad EAS exome

AF:

0.0331

Gnomad SAS exome

AF:

0.00115

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000153

Gnomad OTH exome

AF:

0.00219

GnomAD4 exome

AF:

0.00210

AC:

3054

AN:

1453072

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

1435

AN XY:

722876

show subpopulations

Gnomad4 AFR exome

AF:

0.0301

Gnomad4 AMR exome

AF:

0.00274

Gnomad4 ASJ exome

AF:

0.000270

Gnomad4 EAS exome

AF:

0.0372

Gnomad4 SAS exome

AF:

0.00115

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000642

Gnomad4 OTH exome

AF:

0.00456

GnomAD4 genome

AF:

0.0110

AC:

1670

AN:

152308

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

775

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0330

Gnomad4 AMR

AF:

0.00451

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.0357

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00947

Alfa

AF:

0.00547

Hom.:

Bravo

AF:

0.0131

Asia WGS

AF:

0.0200

AC:

AN:

3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 07, 2012	4597-11delA variant in intron 34 of RYR2: This variant has been identified in 12 .8% (25/572) of Asian chromosomes from a broad population by the 1000 Genomes pr oject (dbSNP rs3841805). -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 03, 2020	Variant summary: RYR2 c.4597-11delA alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0053 in 244908 control chromosomes in the gnomAD database, including 27 homozygotes. The observed variant frequency is approximately 89 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4597-11delA in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Catecholaminergic polymorphic ventricular tachycardia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 15, 2018

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2014

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

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