rs16835237

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.849-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,609,586 control chromosomes in the GnomAD database, including 11,647 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1118 hom., cov: 32)

Exomes 𝑓: 0.11 ( 10529 hom. )

Consequence

RYR2
NM_001035.3 splice_region, intron

Scores

Splicing: ADA: 0.00008724

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.429

Publications

14 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=-0.72).

BP6

Variant 1-237423084-T-C is Benign according to our data. Variant chr1-237423084-T-C is described in ClinVar as Benign. ClinVar VariationId is 43834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.849-8T>C		splice_region_variant, intron_variant	Intron 11 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
RYR2	ENST00000366574.7 link	c.849-8T>C	splice_region_variant, intron_variant	Intron 11 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2 link	c.849-8T>C	splice_region_variant, intron_variant	Intron 11 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2 link	n.849-8T>C	splice_region_variant, intron_variant	Intron 11 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15847

AN:

152082

Hom.:

1123

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0640

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.196

Gnomad ASJ

AF:

0.101

Gnomad EAS

AF:

0.274

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.0844

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0946

Gnomad OTH

AF:

0.109

GnomAD2 exomes

AF:

0.147

AC:

36047

AN:

245086

AF XY:

0.141

show subpopulations

Gnomad AFR exome

AF:

0.0666

Gnomad AMR exome

AF:

0.309

Gnomad ASJ exome

AF:

0.108

Gnomad EAS exome

AF:

0.284

Gnomad FIN exome

AF:

0.0904

Gnomad NFE exome

AF:

0.0990

Gnomad OTH exome

AF:

0.127

GnomAD4 exome

AF:

0.108

AC:

156751

AN:

1457386

Hom.:

10529

Cov.:

AF XY:

0.109

AC XY:

78877

AN XY:

724848

show subpopulations

African (AFR)

AF:

0.0626

AC:

2074

AN:

33146

American (AMR)

AF:

0.299

AC:

12995

AN:

43488

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

2760

AN:

25974

East Asian (EAS)

AF:

0.218

AC:

8632

AN:

39658

South Asian (SAS)

AF:

0.166

AC:

14147

AN:

85250

European-Finnish (FIN)

AF:

0.0925

AC:

4933

AN:

53350

Middle Eastern (MID)

AF:

0.150

AC:

865

AN:

5754

European-Non Finnish (NFE)

AF:

0.0930

AC:

103331

AN:

1110562

Other (OTH)

AF:

0.117

AC:

7014

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

6401

12803

19204

25606

32007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4056

8112

12168

16224

20280

<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:

0.104

AC:

15862

AN:

152200

Hom.:

1118

Cov.:

AF XY:

0.107

AC XY:

7963

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0643

AC:

2668

AN:

41516

American (AMR)

AF:

0.196

AC:

3003

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

350

AN:

3470

East Asian (EAS)

AF:

0.274

AC:

1419

AN:

5180

South Asian (SAS)

AF:

0.164

AC:

792

AN:

4824

European-Finnish (FIN)

AF:

0.0844

AC:

895

AN:

10608

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0946

AC:

6434

AN:

67996

Other (OTH)

AF:

0.109

AC:

230

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

695

1389

2084

2778

3473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

186

372

558

744

930

<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:

0.102

Hom.:

1961

Bravo

AF:

0.114

Asia WGS

AF:

0.195

AC:

675

AN:

3478

EpiCase

AF:

0.102

EpiControl

AF:

0.102

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 12, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 16, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

849-8T>C in Intron 11 of RYR2: This variant has been classified as benign based on high population frequency (MAF=0.164, rs16835237) -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

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

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiomyopathy

Benign:1

Mar 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arrhythmogenic right ventricular dysplasia 2

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Dec 08, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

0.43

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000087

dbscSNV1_RF

Benign

0.0060

SpliceAI score (max)

0.10

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