CASP8

caspase 8, the group of Caspases|Death effector domain containing|Ripoptosome|Death inducing signaling complex

Basic information

Region (hg38): 2:201233443-201361836

Links

ENSG00000064012 ∙ NCBI:841 ∙ OMIM:601763 ∙ HGNC:1509 ∙ Uniprot:Q14790 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autoimmune lymphoproliferative syndrome type 2B (Moderate), mode of inheritance: AR
• autoimmune lymphoproliferative syndrome type 2B (Supportive), mode of inheritance: AR
• autoimmune lymphoproliferative syndrome type 2B (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Caspase 8 defiency	AR	Allergy/Immunology/Infectious	Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial	Allergy/Immunology/Infectious	12353035; 15459299; 19930184; 21447005

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CASP8 gene.

• Autoimmune lymphoproliferative syndrome type 2B (12 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CASP8 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	61	2	65
missense		1	120	4	2	127
nonsense	4		1	1		6
start loss					1	1
frameshift	8	1	1			10
inframe indel			1			1
splice donor/acceptor (+/-2bp)		1	1			2
splice region			4	10		14
non coding		1	50	38	24	113
Total	12	4	176	104	29

Highest pathogenic variant AF is 0.0000131

Variants in CASP8

This is a list of pathogenic ClinVar variants found in the CASP8 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-201233538-A-G		Autoimmune lymphoproliferative syndrome type 2B	Uncertain significance (Apr 27, 2017)
2-201233603-T-G		Autoimmune lymphoproliferative syndrome type 2B	Benign (Jan 12, 2018)
2-201234022-C-A		Autoimmune lymphoproliferative syndrome type 2B	Uncertain significance (Jan 13, 2018)
2-201234056-T-C		Autoimmune lymphoproliferative syndrome type 2B	Uncertain significance (Jan 13, 2018)
2-201257992-T-G			Benign (Nov 10, 2018)
2-201258233-T-C		not specified	Benign (Nov 27, 2018)
2-201258261-T-G			Likely benign (Mar 01, 2023)
2-201258272-A-G		Autoimmune lymphoproliferative syndrome type 2B • not specified	Benign (Jan 19, 2024)
2-201258304-C-A		Autoimmune lymphoproliferative syndrome type 2B	Likely benign (May 21, 2020)
2-201258323-T-A		Autoimmune lymphoproliferative syndrome type 2B	Likely benign (May 21, 2020)
2-201258343-G-A		Autoimmune lymphoproliferative syndrome type 2B	Uncertain significance (Dec 13, 2019)
2-201258367-G-C		Autoimmune lymphoproliferative syndrome type 2B	Likely benign (May 21, 2020)
2-201258385-G-A			Likely benign (Jul 01, 2023)
2-201259467-T-C		Autoimmune lymphoproliferative syndrome type 2B	Uncertain significance (Jun 19, 2020)
2-201266472-C-A			Uncertain significance (Sep 01, 2019)
2-201266509-A-G		Autoimmune lymphoproliferative syndrome type 2B	Uncertain significance (Jun 13, 2022)
2-201266511-G-A		Autoimmune lymphoproliferative syndrome type 2B	Uncertain significance (Mar 18, 2022)
2-201266512-A-G		Autoimmune lymphoproliferative syndrome type 2B	Uncertain significance (Dec 09, 2023)
2-201266519-G-A		Autoimmune lymphoproliferative syndrome type 2B	Likely benign (May 19, 2023)
2-201266529-G-A		Autoimmune lymphoproliferative syndrome type 2B	Uncertain significance (Oct 14, 2019)
2-201266534-T-A		Autoimmune lymphoproliferative syndrome type 2B	Uncertain significance (Oct 03, 2023)
2-201266554-A-G		Autoimmune lymphoproliferative syndrome type 2B	Uncertain significance (May 08, 2022)
2-201266561-G-A		Autoimmune lymphoproliferative syndrome type 2B	Likely benign (Jan 03, 2019)
2-201266570-C-T		Autoimmune lymphoproliferative syndrome type 2B	Likely benign (Jul 06, 2022)
2-201266577-C-T		Autoimmune lymphoproliferative syndrome type 2B	Uncertain significance (Jul 04, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CASP8	protein_coding	protein_coding	ENST00000358485	9	54269

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000372	0.989	125723	0	25	125748	0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.01	226	273	0.828	0.0000133	3585
Missense in Polyphen		50	87.17	0.5736		1178
Synonymous	0.407	98	103	0.949	0.00000527	967
Loss of Function	2.29	13	25.5	0.510	0.00000142	321

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000235	0.000235
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000969	0.0000967
Middle Eastern	0.000109	0.000109
South Asian	0.0000653	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death- inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex. {ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:9006941}.
• Disease: DISEASE: Caspase-8 deficiency (CASP8D) [MIM:607271]: Disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization. {ECO:0000269|PubMed:12353035}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);Legionellosis - Homo sapiens (human);Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human);Viral myocarditis - Homo sapiens (human);p53 signaling pathway - Homo sapiens (human);Apoptosis - multiple species - Homo sapiens (human);Alzheimer,s disease - Homo sapiens (human);Huntington,s disease - Homo sapiens (human);TNF signaling pathway - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);Necroptosis - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Tuberculosis - Homo sapiens (human);IL-17 signaling pathway - Homo sapiens (human);Toxoplasmosis - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Apoptosis - Homo sapiens (human);RIG-I-like receptor signaling pathway - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Nucleotide-binding Oligomerization Domain (NOD) pathway;Regulation of toll-like receptor signaling pathway;miRNA Regulation of DNA Damage Response;Apoptosis Modulation and Signaling;Integrated Breast Cancer Pathway;TNF related weak inducer of apoptosis (TWEAK) Signaling Pathway;Alzheimers Disease;TNF alpha Signaling Pathway;AGE-RAGE pathway;Allograft Rejection;Parkin-Ubiquitin Proteasomal System pathway;Nanomaterial induced apoptosis;Nanoparticle triggered regulated necrosis;Apoptosis;Fas Ligand (FasL) pathway and Stress induction of Heat Shock Proteins (HSP) regulation;Apoptotic Signaling Pathway;Apoptosis Modulation by HSP70;RIG-I-like Receptor Signaling;miRNA regulation of p53 pathway in prostate cancer;DNA Damage Response;Toll-like Receptor Signaling Pathway;RAGE;TWEAK;Signal Transduction;tnfr1 signaling pathway;caspase cascade in apoptosis;induction of apoptosis through dr3 and dr4/5 death receptors;hiv-1 nef: negative effector of fas and tnf;internal ribosome entry pathway;Toll Like Receptor 3 (TLR3) Cascade;Toll-Like Receptors Cascades;Fas;NOD1/2 Signaling Pathway;Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways;NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10;DDX58/IFIH1-mediated induction of interferon-alpha/beta;Regulation of necroptotic cell death;Dimerization of procaspase-8;CLEC7A/inflammasome pathway;CLEC7A (Dectin-1) signaling;Regulation by c-FLIP;Ligand-dependent caspase activation;C-type lectin receptors (CLRs);Caspase activation via extrinsic apoptotic signalling pathway;DroToll-like;Intrinsic Pathway for Apoptosis;Caspase-mediated cleavage of cytoskeletal proteins;Apoptotic cleavage of cellular proteins;Innate Immune System;Immune System;Apoptotic execution phase;Apoptosis;CASP8 activity is inhibited;Regulated Necrosis;Programmed Cell Death;RIPK1-mediated regulated necrosis;fas signaling pathway (cd95);AndrogenReceptor;ceramide signaling pathway;FasL/ CD95L signaling;TNFR1-induced proapoptotic signaling;TNF signaling;TRAIL signaling;TLR3-mediated TICAM1-dependent programmed cell death;Coregulation of Androgen receptor activity;Death Receptor Signalling;Regulation of TNFR1 signaling;Activation, myristolyation of BID and translocation to mitochondria;TNFalpha;TRIF-mediated programmed cell death;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;TNF;Caspase Cascade in Apoptosis;HIV-1 Nef: Negative effector of Fas and TNF-alpha;TRAIL signaling pathway;TNF receptor signaling pathway ;FAS (CD95) signaling pathway;Ceramide signaling pathway;Integrins in angiogenesis (Consensus)

Recessive Scores

• pRec: 0.671

Intolerance Scores

• loftool: 0.274
• rvis_EVS: 0.04
• rvis_percentile_EVS: 57.31

Haploinsufficiency Scores

• pHI: 0.218
• hipred: N
• hipred_score: 0.493
• ghis: 0.495

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Casp8
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; liver/biliary system phenotype; respiratory system phenotype; immune system phenotype; renal/urinary system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); embryo phenotype

Gene ontology

• Biological process: proteolysis;apoptotic process;activation of cysteine-type endopeptidase activity involved in apoptotic process;cell surface receptor signaling pathway;extrinsic apoptotic signaling pathway via death domain receptors;response to cold;regulation of tumor necrosis factor-mediated signaling pathway;natural killer cell activation;macrophage differentiation;response to cobalt ion;response to estradiol;response to lipopolysaccharide;toll-like receptor 3 signaling pathway;response to tumor necrosis factor;TRIF-dependent toll-like receptor signaling pathway;TRAIL-activated apoptotic signaling pathway;suppression by virus of host cysteine-type endopeptidase activity involved in apoptotic process;T cell activation;B cell activation;positive regulation of I-kappaB kinase/NF-kappaB signaling;negative regulation of I-kappaB kinase/NF-kappaB signaling;response to ethanol;positive regulation of macrophage differentiation;positive regulation of proteolysis;proteolysis involved in cellular protein catabolic process;regulation of necroptotic process;syncytiotrophoblast cell differentiation involved in labyrinthine layer development;nucleotide-binding oligomerization domain containing signaling pathway;cellular response to mechanical stimulus;cellular response to organic cyclic compound;death-inducing signaling complex assembly;apoptotic signaling pathway;extrinsic apoptotic signaling pathway;execution phase of apoptosis;activation of cysteine-type endopeptidase activity;activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway;positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway;positive regulation of neuron death;regulation of extrinsic apoptotic signaling pathway via death domain receptors;negative regulation of extrinsic apoptotic signaling pathway via death domain receptors
• Cellular component: nucleoplasm;cytoplasm;mitochondrion;mitochondrial outer membrane;cytosol;cytoskeleton;death-inducing signaling complex;CD95 death-inducing signaling complex;neuron projection;cell body;membrane raft;ripoptosome
• Molecular function: cysteine-type endopeptidase activity;death receptor binding;tumor necrosis factor receptor binding;protein binding;peptidase activity;cysteine-type peptidase activity;ubiquitin protein ligase binding;death effector domain binding;identical protein binding;protein-containing complex binding;scaffold protein binding;cysteine-type endopeptidase activity involved in apoptotic process;cysteine-type endopeptidase activity involved in apoptotic signaling pathway