chr2-201258272-A-C

Variant names:

• chr2-201258272-A-C
• rs3769823
• ENST00000358485.8:c.41A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000358485.8(CASP8):​c.41A>C​(p.Lys14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 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. K14R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: CASP8 ENST00000358485.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.73
• Publications: 112 publications found

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 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome type 2B

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17796433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001080125.2	c.41A>C	p.Lys14Thr	missense_variant	Exon 1 of 9		NP_001073594.1
CASP8	NM_001400642.1	c.41A>C	p.Lys14Thr	missense_variant	Exon 1 of 8		NP_001387571.1
CASP8	NM_001400665.1	c.41A>C	p.Lys14Thr	missense_variant	Exon 1 of 6		NP_001387594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000358485.8	c.41A>C	p.Lys14Thr	missense_variant	Exon 1 of 9	1		ENSP00000351273.4
CASP8	ENST00000437283.5	n.41A>C		non_coding_transcript_exon_variant	Exon 1 of 4	1		ENSP00000407378.1
CASP8	ENST00000264275.9	c.-26-8189A>C		intron_variant	Intron 2 of 9	1		ENSP00000264275.5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 50

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.97
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.99	T
PhyloP100		1.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.11
Sift	Uncertain	0.026	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.73	P
Vest4		0.28
MutPred		0.27		Loss of sheet (P = 0.0228);
MVP		0.74
MPC		0.35
ClinPred		0.80	D
GERP RS		2.8
PromoterAI		-0.22	Neutral
gMVP		0.27
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs3769823; hg19: chr2-202122995;