NM_001035.3:c.14091-25G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001035.3(RYR2):c.14091-25G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,447,184 control chromosomes in the GnomAD database, including 121,790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 10781 hom., cov: 31)

Exomes 𝑓: 0.41 ( 111009 hom. )

Consequence

RYR2
NM_001035.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0840

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 1-237801831-G-A is Benign according to our data. Variant chr1-237801831-G-A is described in ClinVar as Benign. ClinVar VariationId is 257203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.14091-25G>A		intron_variant	Intron 97 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.14091-25G>A	intron_variant	Intron 97 of 104	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2 link	c.14109-25G>A	intron_variant	Intron 98 of 105			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 link	n.*5183-25G>A	intron_variant	Intron 96 of 103	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

AF:

0.367

AC:

54808

AN:

149540

Hom.:

10778

Cov.:

show subpopulations

Gnomad AFR

AF:

0.231

Gnomad AMI

AF:

0.374

Gnomad AMR

AF:

0.347

Gnomad ASJ

AF:

0.483

Gnomad EAS

AF:

0.641

Gnomad SAS

AF:

0.490

Gnomad FIN

AF:

0.406

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.407

Gnomad OTH

AF:

0.389

GnomAD2 exomes

AF:

0.413

AC:

93115

AN:

225654

AF XY:

0.418

show subpopulations

Gnomad AFR exome

AF:

0.215

Gnomad AMR exome

AF:

0.354

Gnomad ASJ exome

AF:

0.492

Gnomad EAS exome

AF:

0.622

Gnomad FIN exome

AF:

0.400

Gnomad NFE exome

AF:

0.403

Gnomad OTH exome

AF:

0.410

GnomAD4 exome

AF:

0.407

AC:

527615

AN:

1297538

Hom.:

111009

Cov.:

AF XY:

0.410

AC XY:

265680

AN XY:

648240

show subpopulations

African (AFR)

AF:

0.208

AC:

6356

AN:

30524

American (AMR)

AF:

0.357

AC:

15103

AN:

42274

Ashkenazi Jewish (ASJ)

AF:

0.494

AC:

11957

AN:

24198

East Asian (EAS)

AF:

0.643

AC:

24744

AN:

38460

South Asian (SAS)

AF:

0.477

AC:

37236

AN:

78062

European-Finnish (FIN)

AF:

0.398

AC:

17372

AN:

43608

Middle Eastern (MID)

AF:

0.487

AC:

2585

AN:

5306

European-Non Finnish (NFE)

AF:

0.397

AC:

389595

AN:

980772

Other (OTH)

AF:

0.417

AC:

22667

AN:

54334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

11903

23805

35708

47610

59513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12038

24076

36114

48152

60190

<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:

0.366

AC:

54823

AN:

149646

Hom.:

10781

Cov.:

AF XY:

0.368

AC XY:

26930

AN XY:

73082

show subpopulations

African (AFR)

AF:

0.231

AC:

9166

AN:

39738

American (AMR)

AF:

0.348

AC:

5279

AN:

15184

Ashkenazi Jewish (ASJ)

AF:

0.483

AC:

1673

AN:

3466

East Asian (EAS)

AF:

0.641

AC:

3270

AN:

5100

South Asian (SAS)

AF:

0.491

AC:

2354

AN:

4790

European-Finnish (FIN)

AF:

0.406

AC:

4183

AN:

10308

Middle Eastern (MID)

AF:

0.473

AC:

139

AN:

294

European-Non Finnish (NFE)

AF:

0.407

AC:

27604

AN:

67766

Other (OTH)

AF:

0.390

AC:

815

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1670

3339

5009

6678

8348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

538

1076

1614

2152

2690

<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:

0.386

Hom.:

1749

Bravo

AF:

0.354

Asia WGS

AF:

0.495

AC:

1711

AN:

3452

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arrhythmogenic right ventricular dysplasia 2

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiac arrhythmia

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

4.4

(source)

DANN

Benign

0.48

PhyloP100

-0.084

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