chr1-237456749-T-C

Position:

• chr1-237456749-T-C

Variant summary

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

The NM_001035.3(RYR2):​c.1612+14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 1,611,822 control chromosomes in the GnomAD database, including 249,649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19675 hom., cov: 30)
  • Exomes 𝑓: 0.56 (229974 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.669

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=-0.85).
• BP6: Variant 1-237456749-T-C is Benign according to our data. Variant chr1-237456749-T-C is described in ClinVar as [Benign]. Clinvar id is 43752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237456749-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.1612+14T>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.1612+14T>C		intron_variant		1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.1612+14T>C		intron_variant		5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.1612+14T>C		intron_variant				ENSP00000499787.2
RYR2	ENST00000659194.3	c.1612+14T>C		intron_variant				ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74754 AN: 151754 Hom.: 19676 Cov.: 30

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.802

Gnomad SAS AF: 0.567

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.496

GnomAD3 exomes AF: 0.557 AC: 138103 AN: 247766 Hom.: 39713 AF XY: 0.559 AC XY: 75147 AN XY: 134440

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.587

Gnomad ASJ exome AF: 0.549

Gnomad EAS exome AF: 0.792

Gnomad SAS exome AF: 0.555

Gnomad FIN exome AF: 0.570

Gnomad NFE exome AF: 0.546

Gnomad OTH exome AF: 0.552

GnomAD4 exome AF: 0.557 AC: 813826 AN: 1459950 Hom.: 229974 Cov.: 37 AF XY: 0.557 AC XY: 404538 AN XY: 726272

Gnomad4 AFR exome AF: 0.297

Gnomad4 AMR exome AF: 0.574

Gnomad4 ASJ exome AF: 0.558

Gnomad4 EAS exome AF: 0.826

Gnomad4 SAS exome AF: 0.550

Gnomad4 FIN exome AF: 0.569

Gnomad4 NFE exome AF: 0.556

Gnomad4 OTH exome AF: 0.553

GnomAD4 genome AF: 0.492 AC: 74777 AN: 151872 Hom.: 19675 Cov.: 30 AF XY: 0.498 AC XY: 36965 AN XY: 74208

Gnomad4 AFR AF: 0.307

Gnomad4 AMR AF: 0.536

Gnomad4 ASJ AF: 0.553

Gnomad4 EAS AF: 0.802

Gnomad4 SAS AF: 0.566

Gnomad4 FIN AF: 0.575

Gnomad4 NFE AF: 0.549

Gnomad4 OTH AF: 0.496

Alfa AF: 0.536 Hom.: 39644

Bravo AF: 0.480

Asia WGS AF: 0.647 AC: 2250 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Eurofins Ntd Llc (ga)	Nov 12, 2014	- -
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	Sep 27, 2011	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

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

Arrhythmogenic right ventricular dysplasia 2 Benign:2

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

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. -

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	-0.85
CADD	Benign	0.13
DANN	Benign	0.56

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: rs2045955; hg19: chr1-237620049;