BCL10
protein-codingBCL10 immune signaling adaptor, the group of CBM complex|Caspase recruitment domain containing
Gene summary
This gene was identified by its translocation in a case of mucosa-associated lymphoid tissue (MALT) lymphoma. The protein encoded by this gene contains a caspase recruitment domain (CARD), and has been shown to induce apoptosis and to activate NF-kappaB. This protein is reported to interact with other CARD domain containing proteins including CARD9, 10, 11 and 14, which are thought to function as upstream regulators in NF-kappaB signaling. This protein is found to form a complex with MALT1, a protein encoded by another gene known to be translocated in MALT lymphoma. MALT1 and this protein are thought to synergize in the activation of NF-kappaB, and the deregulation of either of them may contribute to the same pathogenetic process that leads to the malignancy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~10.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014491
Submitter: ClinGen
BCL10 was first reported in relation to autosomal recessive combined immunodeficiency in 2014 (Torres et al., PMID: 25365219). Three variants (nonsense and splice donor) that have been reported in 3 probands in 3 publications are included in this curation (PMIDs: 25365219, 32008135, 34868072). The mechanism of pathogenicity appears to be loss of function. Individuals affected with combined immunodeficiency due to BCL10 deficiency present in infancy with severe, recurrent infections. While more evidence is needed to establish the full phenotype, patients reported to date have normal total T cell counts but a deficit of memory T cells combined with impaired effector T cell functions, hypogammaglobulinemia, and decreased memory B cells. Low counts of other T cell subsets and NK cells have been described. Heterozygous carriers are reported as unaffected (PMID: 25365219, 34868072). This gene-disease association is supported by biochemical studies, protein interactions, functional and rescue assays, as well as animal models (PMIDs: 10400625, 24074955, 25365219, 32008135, 11163238, 12910267). BCL10 is a part of the CARD11/9–BCL10–MALT1 (CBM) complex. It acts as a signaling molecule transducing the triggering of cell surface antigen receptors to NF-kappaB activation (PMID: 10400625, 24074955). We have previously established other genes within this complex including CARD11 as definitively associated with severe combined immune deficiency. Affected patient cells show altered NF-kappaB signaling that is rescued by wild type (PMID: 25365219, 32008135). BCL10 knockout mice have B cell lymphopenia, reduced B cell proliferation, hypogammaglobulinemia, and impaired immune responses consistent with combined immunodeficiency (PMID: 11163238, 12910267). In summary, BCL10 is definitively associated with combined immunodeficiency due to BCL10 deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date December 15, 2022 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0014491
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014491
Submitter: LiferaOmics
ClinGen SCID-CID GCEP classification: Definitive (approved 12/29/2022). ClinGen curated 3 probands/3 publications with loss-of-function mechanism (PMIDs: 25365219 homozygous splice donor NM_003921.5:c.57+1G>A in consanguineous family), (PMID: 32008135 homozygous nonsense NM_003921.5:c.262C>T; p.Arg88Ter) in consanguineous family; LoE/LoF allele), (PMID:34868072 NM_003921.5:c187A>T;p.(Lys63Term))- Published genetic evidence total = 6.0/12 (segregation points not counted in ClinGen table; case-control = 0). Published experimental evidence total = 6.0/6 supported by complex biochemical function + protein interactions + patient-cell functional alteration/rescue and mouse models (PMIDs cited by ClinGen: 10400625, 24074955, 25365219, 32008135, 11163238, 12910267) - Published overall (ClinGen) = 12.0 (Definitive). Our case contribution: 1 proband, consanguineous parents; family history includes sibling death at 1y with similar features (genotype unknown);predicted LoF: case-level points (AR predicted/proven null, consanguinity) = 1.0; segregation = 0 (no genotyped affected relatives); case-control = 0. Updated total including this case = 13.0 points Overall score = 12.0 points (capped)
Inheritance Pattern: AR
Disease ID:MONDO:0014491
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014491
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: Individuals have been described as susceptible to severe infections, and awareness may allow preventive measures and early and aggressive treatment of infections
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to BCL10 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003921.5. 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 | 43 | 43 | ||||
| missense | 2 | 50 | 52 | |||
| nonsense | 3 | 2 | 5 | |||
| start loss | 1 | 1 | ||||
| frameshift | 13 | 1 | 14 | |||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 4 | |||
| Total | 19 | 0 | 57 | 43 | 0 | 119 |
Highest pathogenic variant AF is 0.000015523765
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003912.1 | 3 | MANE Select | |
| Ensembl | ENSP00000498104.1 | 3 | MANE Select | |
| RefSeq | NP_001307644.1 | 3 | Standard | |
| Ensembl | ENSP00000480561.2 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- T cell receptor signaling pathway - Homo sapiens (human)
- B cell receptor signaling pathway - Homo sapiens (human)
- C-type lectin receptor signaling pathway - Homo sapiens (human)
- Tuberculosis - Homo sapiens (human)
- NF-kappa B signaling pathway - Homo sapiens (human)
Biological Process
- B cell apoptotic process
- neural tube closure
- stimulatory C-type lectin receptor signaling pathway
- toll-like receptor signaling pathway
- response to molecule of bacterial origin
Molecular Function
- protease binding
- transcription coactivator activity
- protein binding
- protein C-terminus binding
- transcription factor binding
Cellular Component
- immunological synapse
- nucleus
- cytoplasm
- lysosome
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000370580
- Coding exons
- 3
- Length
- 10843
- Individuals with no LoFs
- 125736
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125739
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.39 | 80 | 124 | 0.648 | 0.00000637 | 1495 |
| Missense (PolyPhen) | 14 | 30.934 | 0.45258 | 375 | ||
| Synonymous | -0.818 | 52 | 45.0 | 1.16 | 0.00000216 | 473 |
| Loss of Function | 2.09 | 2 | 8.61 | 0.232 | 5.17e-7 | 109 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in adaptive immune response (PubMed:25365219). Promotes apoptosis, pro-caspase-9 maturation and activation of NF- kappa-B via NIK and IKK. May be an adapter protein between upstream TNFR1-TRADD-RIP complex and the downstream NIK-IKK-IKAP complex. Is a substrate for MALT1 (PubMed:18264101). {ECO:0000269|PubMed:18264101, ECO:0000269|PubMed:25365219}.;
- Disease
- DISEASE: Note=A chromosomal aberration involving BCL10 is recurrent in low-grade mucosa-associated lymphoid tissue (MALT lymphoma). Translocation t(1;14)(p22;q32). Although the BCL10/IgH translocation leaves the coding region of BCL10 intact, frequent BCL10 mutations could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions.; DISEASE: Immunodeficiency 37 (IMD37) [MIM:616098]: A form of primary combined immunodeficiency, a group of disorders characterized by severe recurrent infections, with normal numbers or an absence of T and B lymphocytes, and impaired cellular and humoral immunity. IMD37 is characterized by hypogammaglobulinemia without lymphopenia, but with profoundly reduced memory B cells and memory T cells, and increased numbers of circulating naive lymphocytes. Inheritance is autosomal recessive. {ECO:0000269|PubMed:25365219}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Lymphoma, mucosa-associated lymphoid type (MALTOMA) [MIM:137245]: A subtype of non-Hodgkin lymphoma, originating in mucosa-associated lymphoid tissue. MALT lymphomas occur most commonly in the gastro-intestinal tract but have been described in a variety of extranodal sites including the ocular adnexa, salivary gland, thyroid, lung, thymus, and breast. Histologically, they are characterized by an infiltrate of small to medium-sized lymphocytes with abundant cytoplasm and irregularly shaped nuclei. Scattered transformed blasts (large cells) also are present. Non- malignant reactive follicles are observed frequently. A pivotal feature is the presence of lymphoepithelial lesions, with invasion and partial destruction of mucosal glands and crypts by aggregates of tumor cells. {ECO:0000269|PubMed:9989495}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.266
Intolerance Scores
- LoFtool
- 0.289
- RVIS EVS
- 0.28
- RVIS percentile EVS
- 71.08
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.895
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |