1-237456575-A-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.1477-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.53 ( 20698 hom., cov: 0)

Exomes 𝑓: 0.38 ( 1405 hom. )

Failed GnomAD Quality Control

Consequence

RYR2
NM_001035.3 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.43

Publications

1 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 1-237456575-A-AT is Benign according to our data. Variant chr1-237456575-A-AT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.1477-11dupT		intron	N/A	NP_001026.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RYR2	ENST00000366574.7	TSL:1 MANE Select	c.1477-25_1477-24insT	intron	N/A	ENSP00000355533.2
RYR2	ENST00000661330.2		c.1477-25_1477-24insT	intron	N/A	ENSP00000499393.2
RYR2	ENST00000609119.2	TSL:5	n.1477-25_1477-24insT	intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes

AF:

0.528

AC:

78611

AN:

148976

Hom.:

20702

Cov.:

show subpopulations

Gnomad AFR

AF:

0.469

Gnomad AMI

AF:

0.617

Gnomad AMR

AF:

0.544

Gnomad ASJ

AF:

0.546

Gnomad EAS

AF:

0.682

Gnomad SAS

AF:

0.536

Gnomad FIN

AF:

0.542

Gnomad MID

AF:

0.487

Gnomad NFE

AF:

0.544

Gnomad OTH

AF:

0.511

GnomAD2 exomes

AF:

0.379

AC:

53902

AN:

142038

AF XY:

0.378

show subpopulations

Gnomad AFR exome

AF:

0.352

Gnomad AMR exome

AF:

0.387

Gnomad ASJ exome

AF:

0.353

Gnomad EAS exome

AF:

0.439

Gnomad FIN exome

AF:

0.371

Gnomad NFE exome

AF:

0.383

Gnomad OTH exome

AF:

0.365

GnomAD4 exome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.384

AC:

460749

AN:

1198394

Hom.:

1405

Cov.:

AF XY:

0.383

AC XY:

223788

AN XY:

584872

show subpopulations

African (AFR)

AF:

0.340

AC:

8745

AN:

25734

American (AMR)

AF:

0.363

AC:

8846

AN:

24344

Ashkenazi Jewish (ASJ)

AF:

0.364

AC:

7052

AN:

19366

East Asian (EAS)

AF:

0.445

AC:

14188

AN:

31882

South Asian (SAS)

AF:

0.337

AC:

16941

AN:

50240

European-Finnish (FIN)

AF:

0.365

AC:

13668

AN:

37412

Middle Eastern (MID)

AF:

0.353

AC:

1651

AN:

4678

European-Non Finnish (NFE)

AF:

0.388

AC:

371284

AN:

956292

Other (OTH)

AF:

0.379

AC:

18374

AN:

48446

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

14513

29025

43538

58050

72563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15994

31988

47982

63976

79970

<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:

0.528

AC:

78635

AN:

149056

Hom.:

20698

Cov.:

AF XY:

0.529

AC XY:

38362

AN XY:

72500

show subpopulations

African (AFR)

AF:

0.469

AC:

19086

AN:

40732

American (AMR)

AF:

0.544

AC:

8138

AN:

14962

Ashkenazi Jewish (ASJ)

AF:

0.546

AC:

1885

AN:

3454

East Asian (EAS)

AF:

0.682

AC:

3433

AN:

5032

South Asian (SAS)

AF:

0.536

AC:

2526

AN:

4714

European-Finnish (FIN)

AF:

0.542

AC:

5206

AN:

9608

Middle Eastern (MID)

AF:

0.486

AC:

142

AN:

292

European-Non Finnish (NFE)

AF:

0.544

AC:

36608

AN:

67296

Other (OTH)

AF:

0.511

AC:

1051

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1821

3643

5464

7286

9107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

706

1412

2118

2824

3530

<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:

0.461

Hom.:

648

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Aug 19, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RYR2 c.1477-11dupT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.4 in 170484 control chromosomes in the gnomAD database, including 3845 homozygotes. The observed variant frequency is approximately 16047-folds over the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.

Apr 05, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

1477-11_1477-10insT in intron 15 of RYR2: This variant is not expected to have c linical significance because it is located outside the conserved +/- 1, 2 region of the splicing consensus sequence and is part of a polyT stretch. 1477-11_147 7-10insT in intron 15 of RYR2 (allele frequency = n/a)

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

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

Cardiomyopathy

Benign:1

Oct 16, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Apr 15, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

BranchPoint Hunter

3.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over