rs75206601

chr1-237809023-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.607

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 -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	UniProt
RYR2	NM_001035.3	c.14421C>T	p.Asp4807=	synonymous_variant	100/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.14421C>T	p.Asp4807=	synonymous_variant	100/105	1	NM_001035.3	P1

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2442 AN: 152182 Hom.: 66 Cov.: 33

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.: 29 AF XY: 0.00314 AC XY: 424 AN XY: 134952

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.: 65 Cov.: 30 AF XY: 0.00146 AC XY: 1061 AN XY: 726632

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.: 67 Cov.: 33 AF XY: 0.0156 AC XY: 1162 AN XY: 74480

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.: 17

Bravo AF: 0.0189

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	-	- -

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 28, 2023	- -

Cardiomyopathy Benign:2

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

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

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

Other links and lift over

dbSNP: rs75206601; hg19: chr1-237972323; COSMIC: COSV63676779;