rs16835818

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.13476+47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,449,050 control chromosomes in the GnomAD database, including 66,027 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 9830 hom., cov: 32)

Exomes 𝑓: 0.29 ( 56197 hom. )

Consequence

RYR2
NM_001035.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.598

Publications

8 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:

ENSG00000296715 (HGNC:):

ENSG00000296715 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=-0.92).

BP6

Variant 1-237788182-G-A is Benign according to our data. Variant chr1-237788182-G-A is described in ClinVar as [Benign]. Clinvar id is 257200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.13476+47G>A		intron_variant	Intron 92 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.13476+47G>A	intron_variant	Intron 92 of 104	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2 link	c.13494+47G>A	intron_variant	Intron 93 of 105			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 link	n.*4568+47G>A	intron_variant	Intron 91 of 103	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

AF:

0.338

AC:

51381

AN:

151976

Hom.:

9808

Cov.:

show subpopulations

Gnomad AFR

AF:

0.519

Gnomad AMI

AF:

0.166

Gnomad AMR

AF:

0.245

Gnomad ASJ

AF:

0.238

Gnomad EAS

AF:

0.109

Gnomad SAS

AF:

0.226

Gnomad FIN

AF:

0.256

Gnomad MID

AF:

0.299

Gnomad NFE

AF:

0.296

Gnomad OTH

AF:

0.311

GnomAD2 exomes

AF:

0.267

AC:

49709

AN:

185982

AF XY:

0.269

show subpopulations

Gnomad AFR exome

AF:

0.521

Gnomad AMR exome

AF:

0.157

Gnomad ASJ exome

AF:

0.254

Gnomad EAS exome

AF:

0.114

Gnomad FIN exome

AF:

0.263

Gnomad NFE exome

AF:

0.294

Gnomad OTH exome

AF:

0.272

GnomAD4 exome

AF:

0.288

AC:

373606

AN:

1296954

Hom.:

56197

Cov.:

AF XY:

0.287

AC XY:

183848

AN XY:

641316

show subpopulations

African (AFR)

AF:

0.528

AC:

15311

AN:

29020

American (AMR)

AF:

0.162

AC:

5679

AN:

34960

Ashkenazi Jewish (ASJ)

AF:

0.247

AC:

5511

AN:

22340

East Asian (EAS)

AF:

0.101

AC:

3794

AN:

37668

South Asian (SAS)

AF:

0.234

AC:

16431

AN:

70320

European-Finnish (FIN)

AF:

0.256

AC:

12920

AN:

50480

Middle Eastern (MID)

AF:

0.276

AC:

1451

AN:

5260

European-Non Finnish (NFE)

AF:

0.299

AC:

296846

AN:

993038

Other (OTH)

AF:

0.291

AC:

15663

AN:

53868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

12236

24472

36707

48943

61179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.338

AC:

51439

AN:

152096

Hom.:

9830

Cov.:

AF XY:

0.331

AC XY:

24626

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.519

AC:

21519

AN:

41458

American (AMR)

AF:

0.244

AC:

3727

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.238

AC:

825

AN:

3470

East Asian (EAS)

AF:

0.109

AC:

565

AN:

5190

South Asian (SAS)

AF:

0.228

AC:

1098

AN:

4820

European-Finnish (FIN)

AF:

0.256

AC:

2713

AN:

10578

Middle Eastern (MID)

AF:

0.305

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.296

AC:

20103

AN:

67996

Other (OTH)

AF:

0.307

AC:

649

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1647

3293

4940

6586

8233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.310

Hom.:

10785

Bravo

AF:

0.345

Asia WGS

AF:

0.184

AC:

641

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 18, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

-0.92

CADD

Benign

0.0020

(source)

DANN

Benign

0.68

PhyloP100

-0.60

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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rs16835818

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