rs144876996

chr1-237666523-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001035.3(RYR2):c.8448C>T(p.Asp2816=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00806 in 1,611,546 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (109 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.635

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-237666523-C-T is Benign according to our data. Variant chr1-237666523-C-T is described in ClinVar as [Benign]. Clinvar id is 43833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237666523-C-T is described in Lovd as [Benign]. Variant chr1-237666523-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.635 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00669 (1019/152212) while in subpopulation AMR AF= 0.019 (291/15292). AF 95% confidence interval is 0.0172. There are 7 homozygotes in gnomad4. There are 491 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1023 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.8448C>T	p.Asp2816=	synonymous_variant	57/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.8448C>T	p.Asp2816=	synonymous_variant	57/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.8448C>T	p.Asp2816=	synonymous_variant	57/106
RYR2	ENST00000659194.3	c.8448C>T	p.Asp2816=	synonymous_variant	57/105
RYR2	ENST00000609119.2	c.8448C>T	p.Asp2816=	synonymous_variant, NMD_transcript_variant	57/104	5

Frequencies

GnomAD3 genomes AF: 0.00673 AC: 1023 AN: 152094 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00340

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00837

Gnomad OTH AF: 0.00862

GnomAD3 exomes AF: 0.0106 AC: 2616 AN: 246060 Hom.: 49 AF XY: 0.00954 AC XY: 1274 AN XY: 133494

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.0404

Gnomad ASJ exome AF: 0.00211

Gnomad EAS exome AF: 0.000336

Gnomad SAS exome AF: 0.00574

Gnomad FIN exome AF: 0.00382

Gnomad NFE exome AF: 0.00800

Gnomad OTH exome AF: 0.00754

GnomAD4 exome AF: 0.00821 AC: 11977 AN: 1459334 Hom.: 109 Cov.: 30 AF XY: 0.00813 AC XY: 5902 AN XY: 725748

Gnomad4 AFR exome AF: 0.00138

Gnomad4 AMR exome AF: 0.0392

Gnomad4 ASJ exome AF: 0.00219

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00628

Gnomad4 FIN exome AF: 0.00463

Gnomad4 NFE exome AF: 0.00799

Gnomad4 OTH exome AF: 0.00746

GnomAD4 genome AF: 0.00669 AC: 1019 AN: 152212 Hom.: 7 Cov.: 32 AF XY: 0.00660 AC XY: 491 AN XY: 74414

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.0190

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.00340

Gnomad4 NFE AF: 0.00837

Gnomad4 OTH AF: 0.00853

Alfa AF: 0.00769 Hom.: 2

Bravo AF: 0.00849

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2012	Asp2816Asp in Exon 57 of RYR2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 0.8% (54/6602) of Euro pean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs144876996). -

not provided Benign:3

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 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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 16, 2015	- -

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

- -

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

Aug 07, 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	-0.74
Cadd	Benign	1.1
Dann	Benign	0.43

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: rs144876996; hg19: chr1-237829823;