2-201266529-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001372051.1(CASP8):c.43G>A(p.Asp15Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CASP8 NM_001372051.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29199383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP8	NM_001372051.1	c.43G>A	p.Asp15Asn	missense_variant	2/9	ENST00000673742.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000673742.1	c.43G>A	p.Asp15Asn	missense_variant	2/9		NM_001372051.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461838 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727228

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 2B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 14, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CASP8-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 15 of the CASP8 protein (p.Asp15Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	15
Dann	Benign	0.97
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.67	T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	2.0	M;M;M;.;M;.;.;.;.;M;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.60	T;T;D;T;T;T;D;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0040	B;B;B;.;B;.;B;.;B;B;.
Vest4		0.070
MutPred		0.58		Loss of disorder (P = 0.1231);Loss of disorder (P = 0.1231);Loss of disorder (P = 0.1231);Loss of disorder (P = 0.1231);Loss of disorder (P = 0.1231);Loss of disorder (P = 0.1231);.;Loss of disorder (P = 0.1231);Loss of disorder (P = 0.1231);Loss of disorder (P = 0.1231);Loss of disorder (P = 0.1231);
MVP		0.96
MPC		0.40
ClinPred		0.24	T
GERP RS		5.5
Varity_R		0.28
gMVP		0.091

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: rs1947837560; hg19: chr2-202131252;