rs56226196

Positions:

• chr1-237783700-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001035.3(RYR2):​c.11988C>T​(p.Gly3996=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,605,234 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (22 hom., cov: 32)
  • Exomes 𝑓: 0.015 (202 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.343

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=-0.36).
• BP6: Variant 1-237783700-C-T is Benign according to our data. Variant chr1-237783700-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 43717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237783700-C-T is described in Lovd as [Benign]. Variant chr1-237783700-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.343 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0131 (1995/152246) while in subpopulation AMR AF= 0.0179 (273/15282). AF 95% confidence interval is 0.0161. There are 22 homozygotes in gnomad4. There are 919 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1995 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.11988C>T	p.Gly3996=	synonymous_variant	90/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.11988C>T	p.Gly3996=	synonymous_variant	90/105	1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000660292.2	c.12009C>T	p.Gly4003=	synonymous_variant	91/106			ENSP00000499787
RYR2	ENST00000659194.3	c.11976C>T	p.Gly3992=	synonymous_variant	90/105			ENSP00000499653
RYR2	ENST00000609119.2	c.*3080C>T		3_prime_UTR_variant, NMD_transcript_variant	89/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1995 AN: 152128 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00968

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.0117 AC: 2855 AN: 244318 Hom.: 27 AF XY: 0.0123 AC XY: 1629 AN XY: 132416

Gnomad AFR exome AF: 0.00895

Gnomad AMR exome AF: 0.00907

Gnomad ASJ exome AF: 0.00405

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0169

Gnomad FIN exome AF: 0.00308

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0153 AC: 22170 AN: 1452988 Hom.: 202 Cov.: 32 AF XY: 0.0153 AC XY: 11069 AN XY: 721268

Gnomad4 AFR exome AF: 0.00883

Gnomad4 AMR exome AF: 0.00920

Gnomad4 ASJ exome AF: 0.00366

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.0164

Gnomad4 FIN exome AF: 0.00357

Gnomad4 NFE exome AF: 0.0170

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0131 AC: 1995 AN: 152246 Hom.: 22 Cov.: 32 AF XY: 0.0123 AC XY: 919 AN XY: 74440

Gnomad4 AFR AF: 0.00970

Gnomad4 AMR AF: 0.0179

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.00255

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0135 Hom.: 5

Bravo AF: 0.0137

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 04, 2011	- -
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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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	Labcorp Genetics (formerly Invitae), Labcorp	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

- -

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

Jul 28, 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. -

Arrhythmogenic right ventricular dysplasia 2 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.0
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs56226196; hg19: chr1-237947000;