1-237742290-A-T

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.11092-6A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000481 in 1,516,312 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 1 hom. )

Consequence

RYR2
NM_001035.3 splice_region, intron

Scores

Splicing: ADA: 0.00003839

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.0260

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=-0.87).

BP6

Variant 1-237742290-A-T is Benign according to our data. Variant chr1-237742290-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43705.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000276 (41/148720) while in subpopulation AFR AF = 0.000961 (39/40576). AF 95% confidence interval is 0.000722. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.11092-6A>T		splice_region_variant, intron_variant	Intron 79 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.11092-6A>T	splice_region_variant, intron_variant	Intron 79 of 104	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2 link	c.11092-6A>T	splice_region_variant, intron_variant	Intron 79 of 105			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 link	n.*2127-6A>T	splice_region_variant, intron_variant	Intron 77 of 103	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

148720

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000961

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000668

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000210

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000272

AC:

AN:

147078

AF XY:

0.0000387

show subpopulations

Gnomad AFR exome

AF:

0.000372

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000234

AC:

AN:

1367592

Hom.:

Cov.:

AF XY:

0.0000222

AC XY:

AN XY:

675510

show subpopulations

African (AFR)

AF:

0.000868

AC:

AN:

29946

American (AMR)

AF:

0.00

AC:

AN:

31964

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24700

East Asian (EAS)

AF:

0.00

AC:

AN:

35790

South Asian (SAS)

AF:

0.0000399

AC:

AN:

75220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47964

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4806

European-Non Finnish (NFE)

AF:

9.43e-7

AC:

AN:

1060504

Other (OTH)

AF:

0.0000353

AC:

AN:

56698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000276

AC:

AN:

148720

Hom.:

Cov.:

AF XY:

0.000360

AC XY:

AN XY:

72222

show subpopulations

African (AFR)

AF:

0.000961

AC:

AN:

40576

American (AMR)

AF:

0.0000668

AC:

AN:

14966

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5084

South Asian (SAS)

AF:

0.000210

AC:

AN:

4752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67316

Other (OTH)

AF:

0.00

AC:

AN:

2040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000169

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Apr 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Apr 29, 2025

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Apr 14, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia

Benign:1

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Oct 16, 2018

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 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

-0.87

CADD

Benign

0.46

(source)

DANN

Benign

0.46

PhyloP100

-0.026

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000038

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