1-237589774-ATT-AT

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular dysplasia 2
Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
catecholaminergic polymorphic ventricular tachycardia 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RYR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 36741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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	ENST00000661330.2 link	c.3599-18delT	intron_variant	Intron 29 of 105			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 link	n.3599-18delT	intron_variant	Intron 29 of 103	5		ENSP00000499659.2	A0A590UK06

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

GnomAD2 exomes

AF:

0.456

AC:

100785

AN:

221074

AF XY:

0.453

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 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

African (AFR)

AF:

0.108

AC:

3484

AN:

32224

American (AMR)

AF:

0.575

AC:

24991

AN:

43460

Ashkenazi Jewish (ASJ)

AF:

0.452

AC:

11528

AN:

25522

East Asian (EAS)

AF:

0.318

AC:

12385

AN:

38932

South Asian (SAS)

AF:

0.317

AC:

26534

AN:

83604

European-Finnish (FIN)

AF:

0.481

AC:

25300

AN:

52610

Middle Eastern (MID)

AF:

0.352

AC:

2004

AN:

5690

European-Non Finnish (NFE)

AF:

0.452

AC:

490720

AN:

1085146

Other (OTH)

AF:

0.410

AC:

24195

AN:

58962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

18566

37133

55699

74266

92832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14748

29496

44244

58992

73740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.352

AC:

53191

AN:

150972

Hom.:

11151

Cov.:

AF XY:

0.355

AC XY:

26190

AN XY:

73698

show subpopulations

African (AFR)

AF:

0.123

AC:

5031

AN:

41040

American (AMR)

AF:

0.472

AC:

7153

AN:

15154

Ashkenazi Jewish (ASJ)

AF:

0.446

AC:

1543

AN:

3458

East Asian (EAS)

AF:

0.287

AC:

1460

AN:

5084

South Asian (SAS)

AF:

0.299

AC:

1428

AN:

4772

European-Finnish (FIN)

AF:

0.481

AC:

5021

AN:

10430

Middle Eastern (MID)

AF:

0.313

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.447

AC:

30317

AN:

67756

Other (OTH)

AF:

0.370

AC:

771

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1573

3146

4718

6291

7864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

502

1004

1506

2008

2510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

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). -

Nov 12, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

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

PhyloP100

0.47

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over