1-237783664-T-C

Position:

chr1-237783664-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001035.3(RYR2):c.11963-11T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,562,038 control chromosomes in the GnomAD database, including 99,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 9870 hom., cov: 33)

Exomes 𝑓: 0.35 ( 89859 hom. )

Consequence

RYR2
NM_001035.3 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.001738

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 3.41

Variant links:

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]

RYR2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 1-237783664-T-C is Benign according to our data. Variant chr1-237783664-T-C is described in ClinVar as [Benign]. Clinvar id is 43716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237783664-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.11963-11T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.11963-11T>C	splice_polypyrimidine_tract_variant, intron_variant	1	NM_001035.3	P1	Q92736-1
RYR2	ENST00000659194.3 linkuse as main transcript	c.11951-11T>C	splice_polypyrimidine_tract_variant, intron_variant
RYR2	ENST00000660292.2 linkuse as main transcript	c.11984-11T>C	splice_polypyrimidine_tract_variant, intron_variant
RYR2	ENST00000609119.2 linkuse as main transcript	c.*3055-11T>C	splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant	5

Frequencies

GnomAD3 genomes

AF:

0.352

AC:

53570

AN:

152004

Hom.:

9855

Cov.:

show subpopulations

Gnomad AFR

AF:

0.315

Gnomad AMI

AF:

0.290

Gnomad AMR

AF:

0.377

Gnomad ASJ

AF:

0.429

Gnomad EAS

AF:

0.682

Gnomad SAS

AF:

0.434

Gnomad FIN

AF:

0.349

Gnomad MID

AF:

0.364

Gnomad NFE

AF:

0.336

Gnomad OTH

AF:

0.358

GnomAD3 exomes

AF:

0.383

AC:

83586

AN:

218184

Hom.:

16728

AF XY:

0.382

AC XY:

44825

AN XY:

117202

show subpopulations

Gnomad AFR exome

AF:

0.318

Gnomad AMR exome

AF:

0.388

Gnomad ASJ exome

AF:

0.433

Gnomad EAS exome

AF:

0.665

Gnomad SAS exome

AF:

0.425

Gnomad FIN exome

AF:

0.350

Gnomad NFE exome

AF:

0.335

Gnomad OTH exome

AF:

0.381

GnomAD4 exome

AF:

0.350

AC:

492775

AN:

1409916

Hom.:

89859

Cov.:

AF XY:

0.352

AC XY:

245422

AN XY:

697400

show subpopulations

Gnomad4 AFR exome

AF:

0.314

Gnomad4 AMR exome

AF:

0.392

Gnomad4 ASJ exome

AF:

0.439

Gnomad4 EAS exome

AF:

0.693

Gnomad4 SAS exome

AF:

0.429

Gnomad4 FIN exome

AF:

0.345

Gnomad4 NFE exome

AF:

0.327

Gnomad4 OTH exome

AF:

0.370

GnomAD4 genome

AF:

0.352

AC:

53622

AN:

152122

Hom.:

9870

Cov.:

AF XY:

0.356

AC XY:

26486

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.316

Gnomad4 AMR

AF:

0.377

Gnomad4 ASJ

AF:

0.429

Gnomad4 EAS

AF:

0.682

Gnomad4 SAS

AF:

0.434

Gnomad4 FIN

AF:

0.349

Gnomad4 NFE

AF:

0.336

Gnomad4 OTH

AF:

0.361

Alfa

AF:

0.306

Hom.:

1917

Bravo

AF:

0.353

Asia WGS

AF:

0.513

AC:

1784

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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 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. -

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 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. -

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

- -

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

-0.84

CADD

Benign

DANN

Benign

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0017

dbscSNV1_RF

Benign

0.088

SpliceAI score (max)

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over