rs3769824

chr2-201258233-T-Achr2-201258233-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000358485.8(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 ENST00000358485.8 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.196

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]

ACMG classification

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	MANE	UniProt
CASP8	NM_001080125.2	c.2T>A	p.Met1?	start_lost	1/9
CASP8	NM_001400642.1	c.2T>A	p.Met1?	start_lost	1/8
CASP8	NM_001400665.1	c.2T>A	p.Met1?	start_lost	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000358485.8	c.2T>A	p.Met1?	start_lost	1/9	1
CASP8	ENST00000264275.9	c.-26-8228T>A		intron_variant		1
CASP8	ENST00000392258.7	c.-26-8228T>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151158 Hom.: 0 Cov.: 31

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.: 30

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151158 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73818

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	T
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	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0020	T
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.99	D;N;N;N;N;N;N
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.067
Sift	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.12
MutPred		0.98		Gain of ubiquitination at M1 (P = 0.0311);
MVP		0.80
ClinPred		0.13	T
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

Other links and lift over

dbSNP: rs3769824; hg19: chr2-202122956;