CARD11
protein-codingcaspase recruitment domain family member 11, the group of Caspase recruitment domain containing|PDZ domain containing|Membrane associated guanylate kinases|CBM complex
Gene summary
The protein encoded by this gene belongs to the membrane-associated guanylate kinase (MAGUK) family, a class of proteins that functions as molecular scaffolds for the assembly of multiprotein complexes at specialized regions of the plasma membrane. This protein is also a member of the CARD protein family, which is defined by carrying a characteristic caspase-associated recruitment domain (CARD). This protein has a domain structure similar to that of CARD14 protein. The CARD domains of both proteins have been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. When expressed in cells, this protein activated NF-kappaB and induced the phosphorylation of BCL10. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~138.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014081
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0054697
Submitter: ClinGen
CARD11 (i.e., CARMA1) was first reported in relation to autosomal dominant immunodeficiency 11B with atopic dermatitis in 2017 (Ma CA et al., PMID: 28628108). This is a typically early-onset and heterogeneous disease characterized by atopic dermatitis, recurrent respiratory tract infections, asthma, food allergies, variable decreases in antibody levels, elevated serum IgE levels, and eosinophilia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanisms, inheritance patterns, and phenotypic variability for the diseases associated with CARD11. Therefore, the following disease entities have been split into multiple disease entities: autosomal recessive immunodeficiency 11A (i.e., severe combined immunodeficiency due to CARD11 deficiency; OMIM: 615206), autosomal dominant immunodeficiency 11B with atopic dermatitis (OMIM: 617638), and autosomal dominant B-cell expansion with NFkB and T-cell anergy (BENTA; OMIM: 616452). The split curations for immunodeficiency 11A and BENTA have been curated separately. Twenty-one variants (missense, canonical splice site, and nonsense) that have been reported in 21 probands in 4 publications (PMIDs: 28628108, 28826773, 30170123, 33202260) are included in this curation. In addition, CARD11 variants segregated with disease in multiple families (PMID: 28628108, 28826773, 30170123). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be dominant negative. This gene-disease association is also supported by expression studies, an animal model, and in vitro functional assays (PMID: 12154356, 12356734, 12818158, 12867038, 28826773, 30170123, 33202260, 34341167). CARD11 has been demonstrated to be expressed in immune cells (PMID: 12818158) and be a positive regulator of NFkB activation (PMID: 12366734) and T-cell activation and proliferation (PMID: 12867038). The dominant-negative effect of CARD11 variants is typically confirmed in vitro in a CARD11-deficient T-cell line based on NFkB activity (PMID: 28628108, 28826773, 30170123, 33202260). These CARD11 variants have also been shown to cause impairment of NFkB activity and T-cell function in patient cells (PMID: 28826773, 33202260). A mouse model expressing a dominant-negative CARD11 variant recapitulated certain aspects of human disease (PMID: 34341167). In summary, CARD11 is definitively associated with autosomal dominant immunodeficiency 11B with atopic dermatitis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0014645
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0054697
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0014645
Submitter: ClinGen
CARD11 was first reported in relation to autosomal dominant B-cell expansion with NFKB and T-cell anergy (BENTA) disease in 2012 (Snow AL et al., PMID: 23129749). This is a heterogeneous disease characterized by polyclonal B-cell lymphocytosis, splenomegaly, lymphadenopathy, and recurrent upper respiratory tract infections. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanisms, inheritance patterns, and phenotypic variability for the diseases associated with CARD11. Therefore, the following disease entities have been split into multiple disease entities: autosomal recessive immunodeficiency 11A (i.e., severe combined immunodeficiency due to CARD11 deficiency; OMIM: 615206), autosomal dominant immunodeficiency 11B with atopic dermatitis (OMIM: 617638), and autosomal dominant B-cell expansion with NFkB and T-cell anergy (BENTA; OMIM: 616452). The split curations for immunodeficiency 11A and immunodeficiency 11B with atopic dermatitis have been curated separately. Six variants (missense and small in-frame deletion variants) that have been reported in 12 probands in 8 publications (PMIDs: 23129749, 25352053, 25930198, 26861442, 28336733, 29963038, 31897776, 34557185) are included in this curation. Of these patients, at last 6 carried de novo variants. The mechanism of pathogenicity is known to be gain of function, which is typically determined based on increased constitutive NFkB activation in vitro. This gene-disease association is also supported by experimental evidence, including expression, protein interaction, and biochemical function studies on CARD11 and assessment of functional alterations by CARD11 variants in vitro in cell lines and patient cells (PMIDs: 12154356, 12356734, 12818158, 25352053). CARD11 has been demonstrated to be specifically expressed in lymphocytes (PMID: 12818158), interact with IKKa/IKKB (PMID: 12154356), and have roles in positive regulation of NFkB activation downstream of receptor activation and lymphocyte proliferation (PMID: 12356734, 12818158). The presence of variants in CARD11 identified in patients with BENTA were found to cause increased constitutive activation of NFkB in vitro in cell lines and patient cells (PMID: 23129749, 25352053, 25930198, 31897776, 34557185). These variants were also associated with increased proliferation in patient T and B cells (PMID: 25352053). In summary, CARD11 is definitively associated with autosomal dominant BENTA. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0054697
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014081
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0054697
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014081
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014645
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014081
Submitter: ClinGen
CARD11 (i.e., CARMA1) was first reported in relation to immunodeficiency 11A (i.e., severe combined immunodeficiency due to CARD11 deficiency) in 2013 (Stepensky P et al., PMID: 23374270). This disease is characterized by infant-onset increased susceptibility to infection with diminished specific T- and B-cell populations (despite normal-sized total T- and B-cell populations) and activity, as well as hypogammaglobulinemia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanisms, inheritance patterns, and phenotypic variability for the diseases associated with CARD11. Therefore, the following disease entities have been split into multiple disease entities: autosomal recessive immunodeficiency 11A (i.e., severe combined immunodeficiency due to CARD11 deficiency; OMIM: 615206), autosomal dominant immunodeficiency 11B with atopic dermatitis (OMIM: 617638), and autosomal dominant B-cell expansion with NFkB and T-cell anergy (BENTA; OMIM: 616452). The split curations for immunodeficiency 11B with atopic dermatitis and BENTA have been curated separately. Four variants (three nonsense and one large intragenic deletion) that have been reported as homozygous in four probands in four publications (PMIDs: 23374270, 23561803, 26289640, 32815076) are included in this curation. The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by animal models, expression studies, and in vitro functional assays in cell lines and patient cells (PMIDs: 12356734, 12818158, 20233721, 23374270, 23561803, 26289640). Expression studies indicate CARD11 is highly and specifically expressed in the spleen, blood, and immune cells (PMID: 12818158) and functional studies in a cell line indicate a role for CARD11 in positive regulation of NFkB (PMID: 12356734). Furthermore, mouse models deficient in CARD11 recapitulated aspects of patient disease, particularly defects in lymphocyte activation, proliferation, and function and hypogammaglobulinemia (PMID: 12818158, 20233721). Immune cells isolated from patients carrying CARD11 variants displayed defects in activation, proliferation, cytokine production, and NFkB activity (PMID: 23374270, 23561803, 26289640). In summary, CARD11 is definitively associated with autosomal recessive immunodeficiency 11A. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0014645
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Dermatologic; Oncologic
Intervention: Allergy/Immunology/Infectious; Oncologic
Rationale: For Immunodeficiency 11A and 11B and B-cell expansion with NFKB and T-cell anergy, individuals may be prone to frequent infections, and prophylactic measures, as well as early and aggressive treatment of infections may be beneficial; For B-cell expansion with NFKB and T-cell anergy, individuals may be predisposed to B cell malignancy, and awareness may allow early recognition and management; HSCT has been described in Congenital B cell lymphocytosis
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CARD11 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_032415.7. 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 | 7 | 327 | 9 | 343 | ||
| missense | 4 | 21 | 475 | 151 | 2 | 653 |
| nonsense | 9 | 2 | 5 | 16 | ||
| start loss | 2 | 2 | ||||
| frameshift | 6 | 1 | 3 | 10 | ||
| splice donor/acceptor (+/-2bp) | 16 | 4 | 20 | |||
| Total | 19 | 40 | 496 | 478 | 11 | 1044 |
Highest pathogenic variant AF is 0.0000065720296
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_115791.3 | 24 | MANE Select | |
| Ensembl | ENSP00000380150.4 | 24 | MANE Select | |
| RefSeq | NP_001311210.1 | 24 | Standard | |
| Ensembl | ENSP00000347695.3 | 7 | 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)
- NF-kappa B signaling pathway - Homo sapiens (human)
- B Cell Receptor Signaling Pathway
- T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection
Biological Process
- positive regulation of cytokine production
- stimulatory C-type lectin receptor signaling pathway
- immunoglobulin production
- I-kappaB kinase/NF-kappaB signaling
- B cell differentiation
Molecular Function
- guanylate kinase activity
- protein binding
- CARD domain binding
Cellular Component
- immunological synapse
- cytoplasm
- cytosol
- plasma membrane
- CBM complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000396946
- Coding exons
- 24
- Length
- 137805
- Individuals with no LoFs
- 125733
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 14
- Defined
- 125747
- p
- 0.0000557
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.54 | 481 | 755 | 0.637 | 0.0000518 | 7561 |
| Missense (PolyPhen) | 97 | 231.77 | 0.41851 | 2312 | ||
| Synonymous | -1.32 | 354 | 324 | 1.09 | 0.0000235 | 2223 |
| Loss of Function | 6.45 | 8 | 63.5 | 0.126 | 0.00000364 | 674 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.000080 | 0.000079 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in the costimulatory signal essential for T- cell receptor (TCR)-mediated T-cell activation. Its binding to DPP4 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner. Activates NF-kappa-B via BCL10 and IKK. Stimulates the phosphorylation of BCL10. Also activates the TORC1 signaling pathway. {ECO:0000269|PubMed:11278692, ECO:0000269|PubMed:11356195, ECO:0000269|PubMed:12356734, ECO:0000269|PubMed:28628108}.;
- Disease
- DISEASE: B-cell expansion with NFKB and T-cell anergy (BENTA) [MIM:616452]: An autosomal dominant condition characterized by onset in infancy of splenomegaly and polyclonal expansion of B cells, resulting in peripheral lymphocytosis. Affected individuals also show mild immune dysfunction, including some defective antibody responses and T-cell anergy. There may be a predisposition to the development of B-cell malignancy. {ECO:0000269|PubMed:23129749, ECO:0000269|PubMed:28628108}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Immunodeficiency 11 A (IMD11A) [MIM:615206]: An autosomal recessive primary immunodeficiency characterized by normal numbers of T and B-lymphocytes, but defective intracellular signaling. There is a block in B-cell differentiation with increased numbers of transitional B-cells and hypogammaglobulinemia, as well as decreased numbers of regulatory T-cells and defects in T-cell function. {ECO:0000269|PubMed:23374270, ECO:0000269|PubMed:23561803}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Immunodeficiency 11B with atopic dermatitis (IMD11B) [MIM:617638]: An autosomal dominant disorder of immune dysfunction characterized by onset of moderate to severe atopic dermatitis in early childhood. Some patients may have recurrent infections and other variable immune abnormalities. Laboratory studies show defects in T-cell activation, increased IgE, and eosinophilia. {ECO:0000269|PubMed:28628108}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.273
Intolerance Scores
- LoFtool
- 0.251
- RVIS EVS
- -1.39
- RVIS percentile EVS
- 4.33
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.810
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |