dbSNP rs779631412: RYR2:c.309+9_309+13delTCTTA (chr1-237364379-CATCTT-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_001035.3(RYR2):c.309+9_309+13delTCTTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,522,492 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

RYR2
NM_001035.3 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.979

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 -10 ACMG points.

BP6

Variant 1-237364379-CATCTT-C is Benign according to our data. Variant chr1-237364379-CATCTT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 412825.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000226 (31/1371016) while in subpopulation MID AF = 0.000538 (3/5576). AF 95% confidence interval is 0.000146. There are 0 homozygotes in GnomAdExome4. There are 18 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.309+9_309+13delTCTTA		intron_variant	Intron 5 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
RYR2	ENST00000366574.7 link	c.309+8_309+12delATCTT	splice_region_variant, intron_variant	Intron 5 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2 link	c.309+8_309+12delATCTT	splice_region_variant, intron_variant	Intron 5 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2 link	n.309+8_309+12delATCTT	splice_region_variant, intron_variant	Intron 5 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151374

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000640

AC:

AN:

203094

AF XY:

0.0000548

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000167

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000913

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1371016

Hom.:

AF XY:

0.0000264

AC XY:

AN XY:

682752

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31200

American (AMR)

AF:

0.000171

AC:

AN:

40938

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25070

East Asian (EAS)

AF:

0.00

AC:

AN:

37696

South Asian (SAS)

AF:

0.00

AC:

AN:

79592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51056

Middle Eastern (MID)

AF:

0.000538

AC:

AN:

5576

European-Non Finnish (NFE)

AF:

0.0000192

AC:

AN:

1043000

Other (OTH)

AF:

0.0000176

AC:

AN:

56888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.409

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:

0.0000198

AC:

AN:

151476

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73996

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41334

American (AMR)

AF:

0.0000658

AC:

AN:

15192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67812

Other (OTH)

AF:

0.00

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

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:

0.0000434

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Dec 15, 2024

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

PhyloP100

0.98

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over