rs3841805

chr1-237602011-TA-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.487

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High AC in GnomAd at 1674 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.4597-11del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.4597-11del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.4597-11del		splice_polypyrimidine_tract_variant, intron_variant
RYR2	ENST00000660292.2	c.4597-11del		splice_polypyrimidine_tract_variant, intron_variant
RYR2	ENST00000609119.2	c.4597-11del		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1674 AN: 152190 Hom.: 29 Cov.: 33

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.: 27 AF XY: 0.00432 AC XY: 573 AN XY: 132786

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.: 61 Cov.: 29 AF XY: 0.00199 AC XY: 1435 AN XY: 722876

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.: 29 Cov.: 33 AF XY: 0.0104 AC XY: 775 AN XY: 74480

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.: 2

Bravo AF: 0.0131

Asia WGS AF: 0.0200 AC: 68 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, 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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Invitae

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

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

Other links and lift over

dbSNP: rs3841805; hg19: chr1-237765311;