1-237794009-A-C

Position:

• chr1-237794009-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000366574.7(RYR2):​c.13913+12A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 1,601,696 control chromosomes in the GnomAD database, including 384,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35105 hom., cov: 32)
  • Exomes 𝑓: 0.69 (349144 hom.)
• Consequence: RYR2 ENST00000366574.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.00600

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-237794009-A-C is Benign according to our data. Variant chr1-237794009-A-C is described in ClinVar as [Benign]. Clinvar id is 43732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237794009-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.13913+12A>C		intron_variant		ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.13913+12A>C		intron_variant		1	NM_001035.3	ENSP00000355533	P1

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102503 AN: 151808 Hom.: 35082 Cov.: 32

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.761

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.954

Gnomad SAS AF: 0.844

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.672

Gnomad OTH AF: 0.651

GnomAD3 exomes AF: 0.732 AC: 179175 AN: 244682 Hom.: 66822 AF XY: 0.732 AC XY: 97116 AN XY: 132628

Gnomad AFR exome AF: 0.598

Gnomad AMR exome AF: 0.823

Gnomad ASJ exome AF: 0.654

Gnomad EAS exome AF: 0.947

Gnomad SAS exome AF: 0.846

Gnomad FIN exome AF: 0.707

Gnomad NFE exome AF: 0.672

Gnomad OTH exome AF: 0.697

GnomAD4 exome AF: 0.690 AC: 1000578 AN: 1449770 Hom.: 349144 Cov.: 28 AF XY: 0.694 AC XY: 501080 AN XY: 721584

Gnomad4 AFR exome AF: 0.595

Gnomad4 AMR exome AF: 0.815

Gnomad4 ASJ exome AF: 0.652

Gnomad4 EAS exome AF: 0.950

Gnomad4 SAS exome AF: 0.840

Gnomad4 FIN exome AF: 0.702

Gnomad4 NFE exome AF: 0.668

Gnomad4 OTH exome AF: 0.689

GnomAD4 genome AF: 0.675 AC: 102572 AN: 151926 Hom.: 35105 Cov.: 32 AF XY: 0.682 AC XY: 50605 AN XY: 74224

Gnomad4 AFR AF: 0.599

Gnomad4 AMR AF: 0.742

Gnomad4 ASJ AF: 0.639

Gnomad4 EAS AF: 0.954

Gnomad4 SAS AF: 0.844

Gnomad4 FIN AF: 0.694

Gnomad4 NFE AF: 0.672

Gnomad4 OTH AF: 0.655

Alfa AF: 0.682 Hom.: 18285

Bravo AF: 0.675

Asia WGS AF: 0.872 AC: 3028 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 16, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2014	- -
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, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Arrhythmogenic right ventricular dysplasia 2 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	Genome-Nilou Lab	Nov 07, 2021	- -

Cardiac arrhythmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.4
DANN	Benign	0.72

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: rs790900; hg19: chr1-237957309;