NM_001035.3:c.464-8A>C

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.464-8A>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 0.261 in 1,595,424 control chromosomes in the GnomAD database, including 59,200 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 0.33 ( 9495 hom., cov: 32)

Exomes 𝑓: 0.25 ( 49705 hom. )

Consequence

RYR2
NM_001035.3 splice_region, intron

Scores

Splicing: ADA: 0.00002350

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -2.49

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=-0.89).

BP6

Variant 1-237377315-A-C is Benign according to our data. Variant chr1-237377315-A-C is described in ClinVar as Benign. ClinVar VariationId is 43790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.464-8A>C		splice_region_variant, intron_variant	Intron 7 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.464-8A>C	splice_region_variant, intron_variant	Intron 7 of 104	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2 link	c.464-8A>C	splice_region_variant, intron_variant	Intron 7 of 105			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 link	n.464-8A>C	splice_region_variant, intron_variant	Intron 7 of 103	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

AF:

0.332

AC:

50500

AN:

151912

Hom.:

9467

Cov.:

show subpopulations

Gnomad AFR

AF:

0.501

Gnomad AMI

AF:

0.203

Gnomad AMR

AF:

0.322

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.442

Gnomad SAS

AF:

0.216

Gnomad FIN

AF:

0.371

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.237

Gnomad OTH

AF:

0.316

GnomAD2 exomes

AF:

0.290

AC:

69503

AN:

239434

AF XY:

0.279

show subpopulations

Gnomad AFR exome

AF:

0.503

Gnomad AMR exome

AF:

0.350

Gnomad ASJ exome

AF:

0.180

Gnomad EAS exome

AF:

0.435

Gnomad FIN exome

AF:

0.367

Gnomad NFE exome

AF:

0.236

Gnomad OTH exome

AF:

0.276

GnomAD4 exome

AF:

0.253

AC:

365205

AN:

1443394

Hom.:

49705

Cov.:

AF XY:

0.251

AC XY:

179856

AN XY:

717104

show subpopulations

African (AFR)

AF:

0.509

AC:

16709

AN:

32830

American (AMR)

AF:

0.344

AC:

14626

AN:

42506

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

4606

AN:

25534

East Asian (EAS)

AF:

0.479

AC:

18864

AN:

39374

South Asian (SAS)

AF:

0.210

AC:

17552

AN:

83398

European-Finnish (FIN)

AF:

0.357

AC:

18954

AN:

53042

Middle Eastern (MID)

AF:

0.223

AC:

1262

AN:

5648

European-Non Finnish (NFE)

AF:

0.234

AC:

257250

AN:

1101456

Other (OTH)

AF:

0.258

AC:

15382

AN:

59606

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

12731

25462

38194

50925

63656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9096

18192

27288

36384

45480

<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:

0.333

AC:

50567

AN:

152030

Hom.:

9495

Cov.:

AF XY:

0.336

AC XY:

24998

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.501

AC:

20758

AN:

41442

American (AMR)

AF:

0.323

AC:

4921

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

627

AN:

3470

East Asian (EAS)

AF:

0.442

AC:

2281

AN:

5164

South Asian (SAS)

AF:

0.216

AC:

1045

AN:

4828

European-Finnish (FIN)

AF:

0.371

AC:

3925

AN:

10576

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.237

AC:

16098

AN:

67980

Other (OTH)

AF:

0.311

AC:

657

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1629

3258

4888

6517

8146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

474

948

1422

1896

2370

<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:

0.265

Hom.:

17859

Bravo

AF:

0.341

Asia WGS

AF:

0.325

AC:

1128

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Dec 01, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 22, 2013

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 12, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:3

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. -

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arrhythmogenic right ventricular dysplasia 2

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Mar 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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. -

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

-0.89

CADD

Benign

0.13

(source)

DANN

Benign

0.53

PhyloP100

-2.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000024

dbscSNV1_RF

Benign

0.0020

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