2-201284825-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001372051.1(CASP8):c.812C>T(p.Thr271Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 151,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T271S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CASP8 NM_001372051.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14247969).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP8	NM_001372051.1	c.812C>T	p.Thr271Ile	missense_variant	8/9	ENST00000673742.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000673742.1	c.812C>T	p.Thr271Ile	missense_variant	8/9		NM_001372051.1	P1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151426 Hom.: 0 Cov.: 32

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.: 34

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151426 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73914

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

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.059
Dann	Benign	0.87
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.56	T;T;T;T;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N
REVEL	Benign	0.047
Sift	Benign	0.099	T;T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T
Polyphen		0.36	B;B;P;P;B;.
Vest4		0.19
MutPred		0.47		.;Loss of disorder (P = 0.0621);.;.;.;.;
MVP		0.59
MPC		0.47
ClinPred		0.24	T
GERP RS		-8.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.40

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: rs1553607264; hg19: chr2-202149548;