rs3820216

Positions:

• chr1-237614528-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001035.3(RYR2):​c.5400A>G​(p.Lys1800=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,614,014 control chromosomes in the GnomAD database, including 686 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (252 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (434 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.269

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=-0.9).
• BP6: Variant 1-237614528-A-G is Benign according to our data. Variant chr1-237614528-A-G is described in ClinVar as [Benign]. Clinvar id is 43805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237614528-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.269 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.5400A>G	p.Lys1800=	synonymous_variant	37/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.5400A>G	p.Lys1800=	synonymous_variant	37/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.5400A>G	p.Lys1800=	synonymous_variant	37/106
RYR2	ENST00000659194.3	c.5400A>G	p.Lys1800=	synonymous_variant	37/105
RYR2	ENST00000609119.2	c.5400A>G	p.Lys1800=	synonymous_variant, NMD_transcript_variant	37/104	5

Frequencies

GnomAD3 genomes AF: 0.0346 AC: 5268 AN: 152184 Hom.: 250 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0730

Gnomad SAS AF: 0.0429

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0278

GnomAD3 exomes AF: 0.0192 AC: 4792 AN: 248946 Hom.: 206 AF XY: 0.0184 AC XY: 2483 AN XY: 135032

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.00687

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.0819

Gnomad SAS exome AF: 0.0390

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000727

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.00796 AC: 11630 AN: 1461712 Hom.: 434 Cov.: 31 AF XY: 0.00855 AC XY: 6219 AN XY: 727138

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.00807

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.0671

Gnomad4 SAS exome AF: 0.0377

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000435

Gnomad4 OTH exome AF: 0.0160

GnomAD4 genome AF: 0.0346 AC: 5276 AN: 152302 Hom.: 252 Cov.: 32 AF XY: 0.0345 AC XY: 2568 AN XY: 74476

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0724

Gnomad4 SAS AF: 0.0425

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.0299

Alfa AF: 0.0112 Hom.: 93

Bravo AF: 0.0383

Asia WGS AF: 0.0670 AC: 232 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Apr 24, 2012	Lys1800Lys in exon 37 of RYR2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 9.5% (303/3184) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS/; rs3820216). -
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	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 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

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 15, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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	-0.90
CADD	Benign	0.14
DANN	Benign	0.45

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: rs3820216; hg19: chr1-237777828; COSMIC: COSV63663138;