Variant rs3769824 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001080125.2(CASP8):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 151,158 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Consequence

CASP8
NM_001080125.2 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.196

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:

CASP8 (HGNC:):

CASP8 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
CASP8	NM_001080125.2 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/9	NP_001073594.1	Q14790-9
CASP8	NM_001400642.1 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/8	NP_001387571.1
CASP8	NM_001400665.1 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/6	NP_001387594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
CASP8	ENST00000358485.8 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/9	1	ENSP00000351273.4	Q14790-9
CASP8	ENST00000264275.9 linkuse as main transcript	c.-26-8228T>A		intron_variant		1	ENSP00000264275.5	Q14790-4
CASP8	ENST00000392258.7 linkuse as main transcript	c.-26-8228T>A		intron_variant		1	ENSP00000376087.3	Q14790-5

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151158

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73818

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

2.9

DANN

Benign

0.79

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.013

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0020

MetaRNN

Uncertain

0.74

MetaSVM

Benign

-0.92

PROVEAN

Benign

-0.080

REVEL

Benign

0.067

Sift

Pathogenic

0.0

Polyphen

0.0

Vest4

0.12

MutPred

0.98

Gain of ubiquitination at M1 (P = 0.0311);

MVP

0.80

ClinPred

0.13

GERP RS

0.58

gMVP

0.36

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over