Genetic Variant RYR2:c.3599-9delT (chr1-237589774-AT-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001035.3(RYR2):c.3599-9delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 11151 hom., cov: 0)

Exomes 𝑓: 0.44 ( 135317 hom. )

Consequence

RYR2
NM_001035.3 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.467

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 1-237589774-AT-A is Benign according to our data. Variant chr1-237589774-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 36741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237589774-AT-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.3599-9delT		intron_variant	Intron 29 of 104	ENST00000366574.7	NP_001026.2	Q92736-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR2	ENST00000366574.7 link	c.3599-18delT	intron_variant	Intron 29 of 104	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000609119.2 link	n.3599-18delT	intron_variant	Intron 29 of 103	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000660292.2 link	c.3599-18delT	intron_variant	Intron 29 of 105			ENSP00000499787.2	A0A590UKB7
RYR2	ENST00000659194.3 link	c.3599-18delT	intron_variant	Intron 29 of 104			ENSP00000499653.3	A0A590UJZ8

Frequencies

GnomAD3 genomes

AF:

0.352

AC:

53178

AN:

150862

Hom.:

11148

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.416

Gnomad AMR

AF:

0.472

Gnomad ASJ

AF:

0.446

Gnomad EAS

AF:

0.287

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.481

Gnomad MID

AF:

0.324

Gnomad NFE

AF:

0.447

Gnomad OTH

AF:

0.374

GnomAD3 exomes

AF:

0.456

AC:

100785

AN:

221074

Hom.:

22370

AF XY:

0.453

AC XY:

54036

AN XY:

119364

show subpopulations

Gnomad AFR exome

AF:

0.136

Gnomad AMR exome

AF:

0.608

Gnomad ASJ exome

AF:

0.482

Gnomad EAS exome

AF:

0.309

Gnomad SAS exome

AF:

0.363

Gnomad FIN exome

AF:

0.509

Gnomad NFE exome

AF:

0.479

Gnomad OTH exome

AF:

0.476

GnomAD4 exome

AF:

0.436

AC:

621141

AN:

1426150

Hom.:

135317

Cov.:

AF XY:

0.433

AC XY:

307250

AN XY:

709776

show subpopulations

Gnomad4 AFR exome

AF:

0.108

Gnomad4 AMR exome

AF:

0.575

Gnomad4 ASJ exome

AF:

0.452

Gnomad4 EAS exome

AF:

0.318

Gnomad4 SAS exome

AF:

0.317

Gnomad4 FIN exome

AF:

0.481

Gnomad4 NFE exome

AF:

0.452

Gnomad4 OTH exome

AF:

0.410

GnomAD4 genome

AF:

0.352

AC:

53191

AN:

150972

Hom.:

11151

Cov.:

AF XY:

0.355

AC XY:

26190

AN XY:

73698

show subpopulations

Gnomad4 AFR

AF:

0.123

Gnomad4 AMR

AF:

0.472

Gnomad4 ASJ

AF:

0.446

Gnomad4 EAS

AF:

0.287

Gnomad4 SAS

AF:

0.299

Gnomad4 FIN

AF:

0.481

Gnomad4 NFE

AF:

0.447

Gnomad4 OTH

AF:

0.370

Alfa

AF:

0.330

Hom.:

1497

Bravo

AF:

0.346

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Sep 27, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 12, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in ARVC, POSTMORTEM, CPVT panel(s). -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 12, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy

Benign:1

Mar 04, 2014

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 20, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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

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

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

1-237589774-ATT-AT

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