chr1-237709587-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001035.3(RYR2):c.10230+20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,519,598 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 19 hom., cov: 32)

Exomes 𝑓: 0.014 ( 160 hom. )

Consequence

RYR2
NM_001035.3 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.618

Publications

4 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=-0.85).

BP6

Variant 1-237709587-T-C is Benign according to our data. Variant chr1-237709587-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 36728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237709587-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 36728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237709587-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 36728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237709587-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 36728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237709587-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 36728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237709587-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 36728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237709587-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 36728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237709587-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 36728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237709587-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 36728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237709587-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 36728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0114 (1736/152212) while in subpopulation AMR AF = 0.0157 (240/15292). AF 95% confidence interval is 0.0141. There are 19 homozygotes in GnomAd4. There are 800 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1736 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.10230+20T>C		intron_variant	Intron 70 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.10230+20T>C	intron_variant	Intron 70 of 104	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2 link	c.10230+20T>C	intron_variant	Intron 70 of 105			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 link	n.*1265+20T>C	intron_variant	Intron 68 of 103	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1731

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00616

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0137

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.0112

AC:

2493

AN:

222208

AF XY:

0.0119

show subpopulations

Gnomad AFR exome

AF:

0.00464

Gnomad AMR exome

AF:

0.00866

Gnomad ASJ exome

AF:

0.00974

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00271

Gnomad NFE exome

AF:

0.0153

Gnomad OTH exome

AF:

0.0139

GnomAD4 exome

AF:

0.0142

AC:

19426

AN:

1367386

Hom.:

160

Cov.:

AF XY:

0.0143

AC XY:

9746

AN XY:

683224

show subpopulations

African (AFR)

AF:

0.00567

AC:

179

AN:

31562

American (AMR)

AF:

0.00844

AC:

356

AN:

42178

Ashkenazi Jewish (ASJ)

AF:

0.00824

AC:

207

AN:

25136

East Asian (EAS)

AF:

0.0000514

AC:

AN:

38908

South Asian (SAS)

AF:

0.0144

AC:

1168

AN:

81098

European-Finnish (FIN)

AF:

0.00327

AC:

172

AN:

52570

Middle Eastern (MID)

AF:

0.0221

AC:

123

AN:

5578

European-Non Finnish (NFE)

AF:

0.0160

AC:

16544

AN:

1033222

Other (OTH)

AF:

0.0118

AC:

675

AN:

57134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

899

1799

2698

3598

4497

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

642

1284

1926

2568

3210

<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:

0.0114

AC:

1736

AN:

152212

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

800

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00626

AC:

260

AN:

41538

American (AMR)

AF:

0.0157

AC:

240

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.0135

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00236

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0148

AC:

1007

AN:

68006

Other (OTH)

AF:

0.0170

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

196

294

392

490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0118

Hom.:

Bravo

AF:

0.0115

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 26, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RYR2 c.10230+20T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The variant allele was found at a frequency of 0.011 in 222208 control chromosomes in the gnomAD database, including 19 homozygotes. The observed variant frequency is approximately 187 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.85

CADD

Benign

1.3

(source)

DANN

Benign

0.39

PhyloP100

-0.62

PromoterAI

0.025

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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