1-237456575-ATTTT-ATTTTTTT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001035.3(RYR2):c.1477-13_1477-11dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

RYR2
NM_001035.3 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.43

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

BP6

Variant 1-237456575-A-ATTT is Benign according to our data. Variant chr1-237456575-A-ATTT is described in ClinVar as Benign. ClinVar VariationId is 928863.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.1477-13_1477-11dupTTT		intron_variant	Intron 15 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
RYR2	ENST00000366574.7 link	c.1477-25_1477-24insTTT	intron_variant	Intron 15 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2 link	c.1477-25_1477-24insTTT	intron_variant	Intron 15 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2 link	n.1477-25_1477-24insTTT	intron_variant	Intron 15 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes

AF:

0.00000671

AC:

AN:

149112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000198

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:

0.000275

AC:

AN:

142038

AF XY:

0.000255

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000274

Gnomad ASJ exome

AF:

0.000585

Gnomad EAS exome

AF:

0.000989

Gnomad FIN exome

AF:

0.000249

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.000339

GnomAD4 exome

AF:

0.0000814

AC:

AN:

1216702

Hom.:

Cov.:

AF XY:

0.0000876

AC XY:

AN XY:

593818

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26172

American (AMR)

AF:

0.000201

AC:

AN:

24866

Ashkenazi Jewish (ASJ)

AF:

0.000102

AC:

AN:

19666

East Asian (EAS)

AF:

0.000775

AC:

AN:

32276

South Asian (SAS)

AF:

0.000472

AC:

AN:

50868

European-Finnish (FIN)

AF:

0.0000791

AC:

AN:

37942

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4730

European-Non Finnish (NFE)

AF:

0.0000340

AC:

AN:

971002

Other (OTH)

AF:

0.000142

AC:

AN:

49180

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.280

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:

0.00000670

AC:

AN:

149194

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72592

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40774

American (AMR)

AF:

0.00

AC:

AN:

14984

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.000198

AC:

AN:

5044

South Asian (SAS)

AF:

0.00

AC:

AN:

4718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67328

Other (OTH)

AF:

0.00

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

648

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 17, 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.1477-13_1477-11dupTTT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00027 in 142038 control chromosomes. The observed variant frequency is approximately 5-folds over the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is benign. In addition, the variant is located in a highly polymorphic repetitive T region. To our knowledge, no occurrence of c.1477-13_1477-11dupTTT in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

BranchPoint Hunter

3.0

Splicing

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over