2-201286440-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_001372051.1(CASP8):c.1305-19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 1,605,558 control chromosomes in the GnomAD database, including 423,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.72 ( 39792 hom., cov: 31)

Exomes 𝑓: 0.72 ( 383827 hom. )

Consequence

CASP8
NM_001372051.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.314

Publications

47 publications found

Variant links:

Genes affected

CASP8 (HGNC:1509): (caspase 8) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. [provided by RefSeq, Jul 2008]

CASP8 Gene-Disease associations (from GenCC):

autoimmune lymphoproliferative syndrome type 2B
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

CASP8 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=-0.9).

BP6

Variant 2-201286440-A-G is Benign according to our data. Variant chr2-201286440-A-G is described in ClinVar as Benign. ClinVar VariationId is 1168127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001372051.1 link	c.1305-19A>G		intron_variant	Intron 8 of 8	ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1 link	c.1305-19A>G		intron_variant	Intron 8 of 8		NM_001372051.1	ENSP00000501268.1		Q14790-1

Frequencies

GnomAD3 genomes

AF:

0.720

AC:

109397

AN:

151906

Hom.:

39753

Cov.:

show subpopulations

Gnomad AFR

AF:

0.786

Gnomad AMI

AF:

0.766

Gnomad AMR

AF:

0.576

Gnomad ASJ

AF:

0.624

Gnomad EAS

AF:

0.699

Gnomad SAS

AF:

0.826

Gnomad FIN

AF:

0.665

Gnomad MID

AF:

0.706

Gnomad NFE

AF:

0.721

Gnomad OTH

AF:

0.676

GnomAD2 exomes

AF:

0.701

AC:

175720

AN:

250534

AF XY:

0.710

show subpopulations

Gnomad AFR exome

AF:

0.788

Gnomad AMR exome

AF:

0.531

Gnomad ASJ exome

AF:

0.612

Gnomad EAS exome

AF:

0.705

Gnomad FIN exome

AF:

0.673

Gnomad NFE exome

AF:

0.721

Gnomad OTH exome

AF:

0.685

GnomAD4 exome

AF:

0.725

AC:

1053181

AN:

1453536

Hom.:

383827

Cov.:

AF XY:

0.727

AC XY:

526293

AN XY:

723536

show subpopulations

African (AFR)

AF:

0.783

AC:

26118

AN:

33358

American (AMR)

AF:

0.539

AC:

24079

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.619

AC:

16137

AN:

26068

East Asian (EAS)

AF:

0.681

AC:

27017

AN:

39662

South Asian (SAS)

AF:

0.821

AC:

70748

AN:

86152

European-Finnish (FIN)

AF:

0.673

AC:

35489

AN:

52700

Middle Eastern (MID)

AF:

0.673

AC:

3877

AN:

5762

European-Non Finnish (NFE)

AF:

0.730

AC:

806733

AN:

1104970

Other (OTH)

AF:

0.714

AC:

42983

AN:

60164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

12790

25580

38371

51161

63951

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19902

39804

59706

79608

99510

<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:

0.720

AC:

109482

AN:

152022

Hom.:

39792

Cov.:

AF XY:

0.717

AC XY:

53246

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.786

AC:

32588

AN:

41458

American (AMR)

AF:

0.575

AC:

8785

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.624

AC:

2165

AN:

3468

East Asian (EAS)

AF:

0.698

AC:

3613

AN:

5174

South Asian (SAS)

AF:

0.827

AC:

3991

AN:

4826

European-Finnish (FIN)

AF:

0.665

AC:

6994

AN:

10516

Middle Eastern (MID)

AF:

0.711

AC:

209

AN:

294

European-Non Finnish (NFE)

AF:

0.721

AC:

49011

AN:

67982

Other (OTH)

AF:

0.677

AC:

1429

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1561

3122

4684

6245

7806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

844

1688

2532

3376

4220

<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:

0.716

Hom.:

22309

Bravo

AF:

0.713

Asia WGS

AF:

0.788

AC:

2741

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 82% of patients studied by a panel of primary immunodeficiencies. Number of patients: 79. Only high quality variants are reported. -

Autoimmune lymphoproliferative syndrome type 2B

Benign:1

Feb 03, 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

-0.90

CADD

Benign

9.1

(source)

DANN

Benign

0.64

PhyloP100

0.31

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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