chr1-237659982-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001035.3(RYR2):c.8209-3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000745 in 1,571,196 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

RYR2
NM_001035.3 splice_region, intron

Scores

Splicing: ADA: 0.02390

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: -0.396

Publications

0 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 1-237659982-A-G is Benign according to our data. Variant chr1-237659982-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43829.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000434 (66/152196) while in subpopulation AFR AF = 0.00156 (65/41560). AF 95% confidence interval is 0.00126. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 66 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.8209-3A>G		splice_region intron	N/A	NP_001026.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RYR2	ENST00000366574.7	TSL:1 MANE Select	c.8209-3A>G	splice_region intron	N/A	ENSP00000355533.2
RYR2	ENST00000661330.2		c.8209-3A>G	splice_region intron	N/A	ENSP00000499393.2
RYR2	ENST00000609119.2	TSL:5	n.8209-3A>G	splice_region intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000902

AC:

AN:

210540

AF XY:

0.0000610

show subpopulations

Gnomad AFR exome

AF:

0.00138

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000993

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000359

AC:

AN:

1419000

Hom.:

Cov.:

AF XY:

0.0000284

AC XY:

AN XY:

704906

show subpopulations

African (AFR)

AF:

0.00136

AC:

AN:

30994

American (AMR)

AF:

0.0000565

AC:

AN:

35402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25014

East Asian (EAS)

AF:

0.00

AC:

AN:

37938

South Asian (SAS)

AF:

0.00

AC:

AN:

76774

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52792

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1095804

Other (OTH)

AF:

0.0000853

AC:

AN:

58602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000434

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

41560

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000561

Hom.:

Bravo

AF:

0.000446

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Sep 24, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.8209-3G>A variant in RYR2 is classified as likely benign because it has been identified in 0.15% (34/21760) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is located in the 3' splice region. Although a subset of computational tools predict a possible splicing impact, this information is not predictive enough to support pathogenicity in the absence of additional data. ACMG/AMP Criteria applied: BA1, PP3.

May 08, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Oct 21, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported in ClinVar (ClinVar Variant ID# 43829; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32746448)

Dilated cardiomyopathy with left ventricular noncompaction

Uncertain:1

Oct 01, 2015

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Cardiomyopathy

Benign:1

Sep 23, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR2-related disorder

Benign:1

Jul 08, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Cardiovascular phenotype

Benign:1

Apr 03, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.7

(source)

DANN

Benign

0.45

PhyloP100

-0.40

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.024

dbscSNV1_RF

Benign

0.44

SpliceAI score (max)

0.17

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over