rs79811945

chr1-237610818-G-Achr1-237610818-G-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.4740G>A(p.Pro1580=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,611,832 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1580P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (49 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.89

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=-0.75).
• BP6: Variant 1-237610818-G-A is Benign according to our data. Variant chr1-237610818-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237610818-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00179 (273/152232) while in subpopulation EAS AF= 0.041 (212/5176). AF 95% confidence interval is 0.0364. There are 7 homozygotes in gnomad4. There are 131 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 266 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.4740G>A	p.Pro1580=	synonymous_variant	36/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.4740G>A	p.Pro1580=	synonymous_variant	36/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.4740G>A	p.Pro1580=	synonymous_variant	36/106
RYR2	ENST00000659194.3	c.4740G>A	p.Pro1580=	synonymous_variant	36/105
RYR2	ENST00000609119.2	c.4740G>A	p.Pro1580=	synonymous_variant, NMD_transcript_variant	36/104	5

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152112 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0409

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00341 AC: 838 AN: 245510 Hom.: 9 AF XY: 0.00316 AC XY: 421 AN XY: 133144

Gnomad AFR exome AF: 0.000399

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.0422

Gnomad SAS exome AF: 0.000966

Gnomad FIN exome AF: 0.000234

Gnomad NFE exome AF: 0.000368

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00173 AC: 2531 AN: 1459600 Hom.: 49 Cov.: 31 AF XY: 0.00173 AC XY: 1256 AN XY: 725892

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000900

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.0509

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.000263

Gnomad4 NFE exome AF: 0.000207

Gnomad4 OTH exome AF: 0.00262

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152232 Hom.: 7 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74438

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0410

Gnomad4 SAS AF: 0.000625

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000458 Hom.: 0

Bravo AF: 0.00193

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 26, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 18, 2019	Variant summary: RYR2 c.4740G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 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 0.0032 in 273374 control chromosomes, predominantly at a frequency of 0.042 within the East Asian subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1680-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.4740G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/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	Feb 18, 2015	p.Pro1580Pro in exon 36 of RYR2: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 5.5% (379/6868) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs79811945). -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 12, 2016	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2016

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 12, 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	-0.75
Cadd	Benign	0.79
Dann	Benign	0.81

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: rs79811945; hg19: chr1-237774118; COSMIC: COSV63687519;