1-237591040-A-G

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.4160+48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,388,112 control chromosomes in the GnomAD database, including 157,584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12981 hom., cov: 28)

Exomes 𝑓: 0.46 ( 144603 hom. )

Consequence

RYR2
NM_001035.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0570

Publications

6 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=-0.91).

BP6

Variant 1-237591040-A-G is Benign according to our data. Variant chr1-237591040-A-G is described in ClinVar as Benign. ClinVar VariationId is 257210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.4160+48A>G		intron_variant	Intron 31 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
RYR2	ENST00000366574.7 link	c.4160+48A>G	intron_variant	Intron 31 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2 link	c.4160+48A>G	intron_variant	Intron 31 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2 link	n.4160+48A>G	intron_variant	Intron 31 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes

AF:

0.392

AC:

57963

AN:

147794

Hom.:

12979

Cov.:

show subpopulations

Gnomad AFR

AF:

0.191

Gnomad AMI

AF:

0.457

Gnomad AMR

AF:

0.497

Gnomad ASJ

AF:

0.469

Gnomad EAS

AF:

0.315

Gnomad SAS

AF:

0.326

Gnomad FIN

AF:

0.485

Gnomad MID

AF:

0.392

Gnomad NFE

AF:

0.483

Gnomad OTH

AF:

0.419

GnomAD2 exomes

AF:

0.453

AC:

81083

AN:

178926

AF XY:

0.449

show subpopulations

Gnomad AFR exome

AF:

0.188

Gnomad AMR exome

AF:

0.610

Gnomad ASJ exome

AF:

0.484

Gnomad EAS exome

AF:

0.311

Gnomad FIN exome

AF:

0.507

Gnomad NFE exome

AF:

0.480

Gnomad OTH exome

AF:

0.479

GnomAD4 exome

AF:

0.459

AC:

569495

AN:

1240214

Hom.:

144603

Cov.:

AF XY:

0.457

AC XY:

280967

AN XY:

614892

show subpopulations

African (AFR)

AF:

0.160

AC:

4804

AN:

30098

American (AMR)

AF:

0.597

AC:

20786

AN:

34802

Ashkenazi Jewish (ASJ)

AF:

0.470

AC:

10045

AN:

21378

East Asian (EAS)

AF:

0.347

AC:

12951

AN:

37354

South Asian (SAS)

AF:

0.331

AC:

23659

AN:

71416

European-Finnish (FIN)

AF:

0.501

AC:

22524

AN:

45000

Middle Eastern (MID)

AF:

0.394

AC:

2020

AN:

5124

European-Non Finnish (NFE)

AF:

0.477

AC:

449701

AN:

942190

Other (OTH)

AF:

0.435

AC:

23005

AN:

52852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

13405

26809

40214

53618

67023

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12390

24780

37170

49560

61950

<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:

0.392

AC:

57958

AN:

147898

Hom.:

12981

Cov.:

AF XY:

0.391

AC XY:

28081

AN XY:

71764

show subpopulations

African (AFR)

AF:

0.191

AC:

7771

AN:

40702

American (AMR)

AF:

0.497

AC:

7225

AN:

14540

Ashkenazi Jewish (ASJ)

AF:

0.469

AC:

1594

AN:

3402

East Asian (EAS)

AF:

0.315

AC:

1552

AN:

4930

South Asian (SAS)

AF:

0.326

AC:

1533

AN:

4698

European-Finnish (FIN)

AF:

0.485

AC:

4707

AN:

9696

Middle Eastern (MID)

AF:

0.377

AC:

107

AN:

284

European-Non Finnish (NFE)

AF:

0.483

AC:

32220

AN:

66722

Other (OTH)

AF:

0.414

AC:

841

AN:

2032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1544

3087

4631

6174

7718

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

536

1072

1608

2144

2680

<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:

0.457

Hom.:

13856

Bravo

AF:

0.395

Asia WGS

AF:

0.286

AC:

959

AN:

3352

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jun 15, 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.

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.91

CADD

Benign

1.8

(source)

DANN

Benign

0.38

PhyloP100

-0.057

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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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