CASP10

protein-coding

caspase 10, the group of Caspases|Death inducing signaling complex |Death effector domain containing

Gene summary

This gene encodes a protein which is 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 which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein cleaves and activates caspases 3 and 7, and the protein itself is processed by caspase 8. Mutations in this gene are associated with type IIA autoimmune lymphoproliferative syndrome, non-Hodgkin lymphoma and gastric cancer. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]

MANE transcript

NM_032977.4

Inheritance

ClinVar variants

P:6U:309B:136

Top phenotype

Autoimmune lymphoproliferative syndrome, type IIA

gnomAD constraint

pLI —, LoF o/e 0.88

Max pathogenic AF

—

Genomic locus

chr2:201,182,872-201,229,428

External References & Databases

Ensembl (ENSG00000003400)

Transcript & Mutation Effects

hg38 • Region Span ~46.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autoimmune lymphoproliferative syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017979

Submitter: Orphanet

autoimmune lymphoproliferative syndrome type 2ALIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011383

Submitter: ClinGen

CASP10 deficiency was first reported as the cause of autoimmune lymphoproliferative syndrome (ALPS) type 2A in 1999 (PMID: 10412980). Patients with this disorder present with hepatosplenomegaly, chronic non-infectious non-malignant lymphadenopathy and the development of autoimmune disorders, in particular anaemia, thrombocytopenia and neutropenia. Characteristic laboratory findings include an increased in double-negative (CD4-/CD8-) alpha/beta T-cells, hypergammaglobulinemia and impaired lymphocyte apoptosis. Nine variants (missense and frameshift) have been reported in multiple probands in multiple publications (PMIDs: 10412980, 16446975, 31309545, 36844186, 17999750, 32599613, 27872624). Five of the nine variants (Ile406Leu, Val410Ile, Tyr466Cys, Leu522Ile, Pro501Leu) have subsequently shown to have high allele frequencies in the population not consistent with a monogenic disorder. The mechanism of pathogenicity is proposed to be dominant-negative. Functional studies demonstrating a dominant-negative effect demonstrated the same results for a rare variant (Leu285Phe) and a common polymorphism (Ile406Leu), therefore the mechanism is not proven (PMID: 16446975). Many reported probands have unaffected parents with the same variant, so penetrance is proposed to be incomplete. Expression studies, protein interaction studies and functional studies confirms the role of CASP10 in apoptosis. CASP10 is expressed in many tissues, including lymphoid organs and lymphocytes (Vincenz et al., 1997 and Wang et al., 2001). CASP10 is recruited to Fas and TNF receptor by FADD (Vincenz et. al, 1997), and is essential for FasL and TRAIL induced apoptosis (Wang et al., 2001) which are known to be defective in other forms of ALPS. Mutated CASP10, which lacks the active site, interferes with FasL and TRAIL induced apoptosis in transfected cells, supporting a dominant-negative model (Wang et al., 2001). Mice lack Casp10 and therefore a mouse model does not exist. Recently Magerus et al. asserted that biallelic mutations that completely abolish caspase-10 have no impact on FAS-induced apoptosis, however this data is not yet published. In summary, there is limited evidence supporting the relationship between CASP10 and autosomal dominant autoimmune lymphoproliferative syndrome (ALPS) type 2A. This classification was approved by the ClinGen PIRD GCEP on the meeting date 19th March 2024 (SOP Version 10).

autoimmune lymphoproliferative syndrome type 2ASTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011383

Submitter: G2P

autoimmune lymphoproliferative syndrome type 2ALIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0011383

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Autoimmune lymphoproliferative syndrome, type IIAAD

Manifestation: Allergy/Immunology/Infectious; Hematologic; Oncologic

Intervention: Allergy/Immunology/Infectious; Oncologic

Rationale: Lymphoproliferation can be suppressed with medications such as corticosteroids, cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil; BMT/HSCT the only curative treatment for ALPS, has to date mostly been reported in patients with severe clinical findings; Surveillance for manifestations of lymphoproliferation and autoimmunity, and specialized imaging studies to detect malignant transformation may be beneficial

Comments: Variants may modify other related disorders

Refs: 10412980; 16537120; 16446975; 17999750; 20301287

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CASP10 variants in ClinVar

13 Conditions Cataloged

Autoimmune lymphoproliferative syndrome type 2ATotal: 478

not specifiedTotal: 129

not providedTotal: 64

CASP10-related disorderTotal: 33

Gastric cancerTotal: 9

Lymphoma, non-Hodgkin, familialTotal: 7

Autoimmune lymphoproliferative syndrome type 1Total: 5

Non-Hodgkin lymphomaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032977.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	112 clinvar		116
missense	1 clinvar		269 clinvar	22 clinvar	1 clinvar	293
nonsense	1 clinvar		10 clinvar			11
start loss						0
frameshift	2 clinvar	2 clinvar	18 clinvar	1 clinvar		23
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	4	2	309	135	1	451

Highest pathogenic variant AF is 0.0000012391129

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032977.4	RefSeq	NP_116759.2	9	MANE Select
ENST00000286186.11	Ensembl	ENSP00000286186.6	9	MANE Select
NM_001206524.2	RefSeq	NP_001193453.1	7	Standard
NM_001206542.2	RefSeq	NP_001193471.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

TNF signaling pathway - Homo sapiens (human)
Tuberculosis - Homo sapiens (human)
Hepatitis B - Homo sapiens (human)
Apoptosis - Homo sapiens (human)
RIG-I-like receptor signaling pathway - Homo sapiens (human)

Biological Process

proteolysis
apoptotic process
activation of cysteine-type endopeptidase activity involved in apoptotic process
cell surface receptor signaling pathway
regulation of apoptotic process

Molecular Function

cysteine-type endopeptidase activity
protein binding
ubiquitin protein ligase binding
death effector domain binding
cysteine-type endopeptidase activity involved in apoptotic process

Cellular Component

cytoplasm
cytosol
CD95 death-inducing signaling complex
ripoptosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000286186
Coding exons: 9
Length: 46526
Individuals with no LoFs: 125554
Homozygous LoFs: 2
Heterozygous LoFs: 192
Defined: 125748
p: 0.000772

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0269	271	272	0.995	0.0000136	3424
Missense (PolyPhen)		79	84.057	0.93984		1091
Synonymous	-0.232	115	112	1.03	0.00000601	1022
Loss of Function	0.529	19	21.7	0.877	0.00000109	256

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.0014	0.0014	notable
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0.0015	0.0015	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.00075	0.00075	rare
South Asian	0.00080	0.00075	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the activation cascade of caspases responsible for apoptosis execution. Recruited to both Fas- and TNFR-1 receptors in a FADD dependent manner. May participate in the granzyme B apoptotic pathways. Cleaves and activates caspase- 3, -4, -6, -7, -8, and -9. Hydrolyzes the small- molecule substrates, Tyr-Val-Ala-Asp-|-AMC and Asp-Glu-Val-Asp-|-AMC. {ECO:0000269|PubMed:11717445}.; FUNCTION: Isoform C is proteolytically inactive. {ECO:0000269|PubMed:11717445}.;
Disease: DISEASE: Autoimmune lymphoproliferative syndrome 2A (ALPS2A) [MIM:603909]: A disorder of apoptosis that manifests in early childhood and results in the accumulation of autoreactive lymphocytes. It is characterized by non-malignant lymphadenopathy with hepatosplenomegaly, and autoimmune hemolytic anemia, thrombocytopenia and neutropenia. {ECO:0000269|PubMed:10412980}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Familial non-Hodgkin lymphoma (NHL) [MIM:605027]: Cancer that starts in cells of the lymph system, which is part of the body's immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever and weight loss. {ECO:0000269|PubMed:12010812}. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Gastric cancer (GASC) [MIM:613659]: A malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease. {ECO:0000269|PubMed:11973654}. Note=The gene represented in this entry is involved in disease pathogenesis.;

Intolerance Scores

LoFtool: 0.454
RVIS EVS: -0.09
RVIS percentile EVS: 46.99

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.502

Gene Damage Prediction

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