2-201285116-G-T

Position:

• chr2-201285116-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001372051.1(CASP8):​c.1103G>T​(p.Gly368Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CASP8 NM_001372051.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.191

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP8	NM_001372051.1	c.1103G>T	p.Gly368Val	missense_variant	8/9	ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1	c.1103G>T	p.Gly368Val	missense_variant	8/9		NM_001372051.1	ENSP00000501268.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T;.;.;.;T
Eigen	Benign	0.020
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.88	D;D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.73	D;D;D;D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	3.1	.;M;.;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0060	D;D;D;D;D;T
Sift4G	Uncertain	0.035	D;D;D;T;D;T
Polyphen		1.0	D;P;D;D;P;.
Vest4		0.21
MutPred		0.79		.;Loss of ubiquitination at K367 (P = 0.0345);.;.;.;.;
MVP		0.89
MPC		1.1
ClinPred		0.99	D
GERP RS		1.1
Varity_R		0.67
gMVP		0.90

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: rs758525204; hg19: chr2-202149839;