2-201266772-G-C

Variant names:

• chr2-201266772-G-C
• rs762297913
• NM_001372051.1:c.286G>C

Variant summary

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

The NM_001372051.1(CASP8):​c.286G>C​(p.Ala96Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. A96S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASP8 NM_001372051.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.25
• Publications: 4 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372051.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	NM_001372051.1	MANE Select	c.286G>C	p.Ala96Pro	missense	Exon 2 of 9	NP_001358980.1	Q14790-1
	CASP8	NM_001080125.2		c.463G>C	p.Ala155Pro	missense	Exon 2 of 9	NP_001073594.1	Q14790-9
	CASP8	NM_001400642.1		c.463G>C	p.Ala155Pro	missense	Exon 2 of 8	NP_001387571.1	A0A8Q3SID9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000673742.1	MANE Select	c.286G>C	p.Ala96Pro	missense	Exon 2 of 9	ENSP00000501268.1	Q14790-1
	CASP8	ENST00000358485.8	TSL:1	c.463G>C	p.Ala155Pro	missense	Exon 2 of 9	ENSP00000351273.4	Q14790-9
	CASP8	ENST00000264275.9	TSL:1	c.286G>C	p.Ala96Pro	missense	Exon 3 of 10	ENSP00000264275.5	Q14790-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.57
Sift	Benign	0.17	T
Sift4G	Benign	0.24	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.51		Gain of disorder (P = 0.0369)
MVP		0.95
MPC		1.2
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.64
gMVP		0.49
Mutation Taster		=67/33	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: rs762297913; hg19: chr2-202131495;