Variant 2-201286440-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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:3

Conservation

PhyloP100: 0.314

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 1168127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201286440-A-G is described in Lovd as [Benign].

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/exons	MANE	UniProt
CASP8	NM_001372051.1 linkuse as main transcript	c.1305-19A>G		intron_variant		ENST00000673742.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000673742.1 linkuse as main transcript	c.1305-19A>G		intron_variant			NM_001372051.1	P1	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

GnomAD3 exomes

AF:

0.701

AC:

175720

AN:

250534

Hom.:

62624

AF XY:

0.710

AC XY:

96282

AN XY:

135514

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 SAS exome

AF:

0.825

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

Gnomad4 AFR exome

AF:

0.783

Gnomad4 AMR exome

AF:

0.539

Gnomad4 ASJ exome

AF:

0.619

Gnomad4 EAS exome

AF:

0.681

Gnomad4 SAS exome

AF:

0.821

Gnomad4 FIN exome

AF:

0.673

Gnomad4 NFE exome

AF:

0.730

Gnomad4 OTH exome

AF:

0.714

GnomAD4 genome

AF:

0.720

AC:

109482

AN:

152022

Hom.:

39792

Cov.:

AF XY:

0.717

AC XY:

53246

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.786

Gnomad4 AMR

AF:

0.575

Gnomad4 ASJ

AF:

0.624

Gnomad4 EAS

AF:

0.698

Gnomad4 SAS

AF:

0.827

Gnomad4 FIN

AF:

0.665

Gnomad4 NFE

AF:

0.721

Gnomad4 OTH

AF:

0.677

Alfa

AF:

0.715

Hom.:

14607

Bravo

AF:

0.713

Asia WGS

AF:

0.788

AC:

2741

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

9.1

DANN

Benign

0.64

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over