1-237742270-CTTTTT-CTTTTTT

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.11092-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,162,062 control chromosomes in the GnomAD database, including 502 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.075 ( 398 hom., cov: 26)

Exomes 𝑓: 0.11 ( 104 hom. )

Consequence

RYR2
NM_001035.3 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0580

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 1-237742270-C-CT is Benign according to our data. Variant chr1-237742270-C-CT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 177986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.11092-11dupT		intron_variant	Intron 79 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
RYR2	ENST00000366574.7 link	c.11092-26_11092-25insT	intron_variant	Intron 79 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2 link	c.11092-26_11092-25insT	intron_variant	Intron 79 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2 link	n.2127-26_2127-25insT	intron_variant	Intron 77 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes

AF:

0.0749

AC:

10375

AN:

138484

Hom.:

398

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0467

Gnomad AMI

AF:

0.0943

Gnomad AMR

AF:

0.0786

Gnomad ASJ

AF:

0.0525

Gnomad EAS

AF:

0.0398

Gnomad SAS

AF:

0.0972

Gnomad FIN

AF:

0.0666

Gnomad MID

AF:

0.0811

Gnomad NFE

AF:

0.0931

Gnomad OTH

AF:

0.0756

GnomAD4 exome

AF:

0.111

AC:

113383

AN:

1023570

Hom.:

104

Cov.:

AF XY:

0.109

AC XY:

55790

AN XY:

510632

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0810

AC:

1865

AN:

23028

American (AMR)

AF:

0.0687

AC:

1589

AN:

23136

Ashkenazi Jewish (ASJ)

AF:

0.0658

AC:

1282

AN:

19478

East Asian (EAS)

AF:

0.0509

AC:

1515

AN:

29774

South Asian (SAS)

AF:

0.109

AC:

6294

AN:

57738

European-Finnish (FIN)

AF:

0.0669

AC:

2588

AN:

38692

Middle Eastern (MID)

AF:

0.0770

AC:

286

AN:

3714

European-Non Finnish (NFE)

AF:

0.119

AC:

93417

AN:

784490

Other (OTH)

AF:

0.104

AC:

4547

AN:

43520

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.366

Heterozygous variant carriers

5370

10740

16109

21479

26849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3724

7448

11172

14896

18620

<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:

0.0749

AC:

10378

AN:

138492

Hom.:

398

Cov.:

AF XY:

0.0746

AC XY:

5009

AN XY:

67102

show subpopulations

African (AFR)

AF:

0.0468

AC:

1710

AN:

36524

American (AMR)

AF:

0.0785

AC:

1093

AN:

13916

Ashkenazi Jewish (ASJ)

AF:

0.0525

AC:

174

AN:

3312

East Asian (EAS)

AF:

0.0397

AC:

192

AN:

4836

South Asian (SAS)

AF:

0.0977

AC:

430

AN:

4400

European-Finnish (FIN)

AF:

0.0666

AC:

537

AN:

8064

Middle Eastern (MID)

AF:

0.0839

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.0931

AC:

5992

AN:

64382

Other (OTH)

AF:

0.0756

AC:

144

AN:

1904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

446

892

1337

1783

2229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

252

378

504

630

<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:

0.0276

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Dec 09, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

11092-12_11092-11delTT in intron 79 of RYR2: This variant is not expected to hav e clinical significance because it is located outside the conserved +/- 1, 2 reg ion of the splicing consensus sequence and as part of a polyT stretch. -

Feb 11, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Dec 10, 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

Aug 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.058

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