rs72549414

Positions:

• chr1-237491873-A-T

Variant summary

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

The ENST00000366574.7(RYR2):​c.1776A>T​(p.Gly592=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,468,978 control chromosomes in the GnomAD database, including 417 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (82 hom., cov: 33)
  • Exomes 𝑓: 0.020 (335 hom.)
• Consequence: RYR2 ENST00000366574.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.0110

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=-0.54).
• BP6: Variant 1-237491873-A-T is Benign according to our data. Variant chr1-237491873-A-T is described in ClinVar as [Benign]. Clinvar id is 43753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237491873-A-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.011 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0279 (4244/152324) while in subpopulation AFR AF= 0.0415 (1723/41566). AF 95% confidence interval is 0.0398. There are 82 homozygotes in gnomad4. There are 2097 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4244 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.1776A>T	p.Gly592=	synonymous_variant	18/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.1776A>T	p.Gly592=	synonymous_variant	18/105	1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000660292.2	c.1776A>T	p.Gly592=	synonymous_variant	18/106			ENSP00000499787
RYR2	ENST00000659194.3	c.1776A>T	p.Gly592=	synonymous_variant	18/105			ENSP00000499653
RYR2	ENST00000609119.2	c.1776A>T	p.Gly592=	synonymous_variant, NMD_transcript_variant	18/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4244 AN: 152206 Hom.: 83 Cov.: 33

Gnomad AFR AF: 0.0415

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0238

Gnomad OTH AF: 0.0277

GnomAD3 exomes AF: 0.0204 AC: 3514 AN: 172218 Hom.: 53 AF XY: 0.0201 AC XY: 1832 AN XY: 91192

Gnomad AFR exome AF: 0.0424

Gnomad AMR exome AF: 0.0183

Gnomad ASJ exome AF: 0.00617

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00671

Gnomad FIN exome AF: 0.0326

Gnomad NFE exome AF: 0.0247

Gnomad OTH exome AF: 0.0239

GnomAD4 exome AF: 0.0203 AC: 26693 AN: 1316654 Hom.: 335 Cov.: 24 AF XY: 0.0199 AC XY: 13056 AN XY: 654634

Gnomad4 AFR exome AF: 0.0431

Gnomad4 AMR exome AF: 0.0178

Gnomad4 ASJ exome AF: 0.00515

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00687

Gnomad4 FIN exome AF: 0.0291

Gnomad4 NFE exome AF: 0.0212

Gnomad4 OTH exome AF: 0.0215

GnomAD4 genome AF: 0.0279 AC: 4244 AN: 152324 Hom.: 82 Cov.: 33 AF XY: 0.0282 AC XY: 2097 AN XY: 74486

Gnomad4 AFR AF: 0.0415

Gnomad4 AMR AF: 0.0261

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.0353

Gnomad4 NFE AF: 0.0238

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.0237 Hom.: 12

Bravo AF: 0.0285

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 21, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2011	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, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 10, 2023	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

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

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.4
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72549414; hg19: chr1-237655173;