CD40
protein-codingCD40 molecule, the group of CD molecules|Tumor necrosis factor receptor superfamily
Gene summary
This gene is a member of the TNF-receptor superfamily. The encoded protein is a receptor on antigen-presenting cells of the immune system and is essential for mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. AT-hook transcription factor AKNA is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions. Adaptor protein TNFR2 interacts with this receptor and serves as a mediator of the signal transduction. The interaction of this receptor and its ligand is found to be necessary for amyloid-beta-induced microglial activation, and thus is thought to be an early event in Alzheimer disease pathogenesis. Mutations affecting this gene are the cause of autosomal recessive hyper-IgM immunodeficiency type 3 (HIGM3). Multiple alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Nov 2014]
- TNFRSF5
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~11.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0011735
Submitter: ClinGen
*CD40* was first reported in relation to autosomal recessive hyper-IgM syndrome type 3 in 2006 (Ferrari S, et al., 2001, PMID: 11675497). CD40 is a cell surface receptor that is expressed on the surface of all mature B cells, the encoded protein is a receptor on antigen-presenting cells of the immune system and is essential for mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. Adaptor protein TNFR2 interacts with this receptor and serves as a mediator of the signal transduction. Deleterious biallelic variation in this gene thus disrupt immature B cells from receiving signal 2 from helper T cells, which is necessary to mature into mature B cells. These patients are characterized by hypogammaglobulinemia with normal or elevated levels of IgM. This gene-disease relationship is supported by both genetic and experimental evidence. At least sixteen variants (missense, splice site, and in frame indels) have been reported in eight probands from seven publications (PMIDs: 24122029, 12584544, 26545377, 25511220, 11675497, 17502893, 22443339) and seven additional affected family members. A role in disease is supported by the function of *CD40* in generating or maintaining human CD21low B cells in vivo (PMID: 34623902), which can be observed as patient B cells defective in isotype switching and IgG/IgA/IgM production (PMID: 11675497). Additionally, a knock out mouse model which mounted IgM responses but no IgG, IgA, and IgE responses to thymus dependent (TD) antigens and *CD40* was shown to be essential for T cell-dependent immunoglobulin class switching and germinal center formation, but not for in vivo T cell-dependent IgM responses and T cell-independent antibody responses (PMID: 7534202). In summary *CD40* is definitively associated with autosomal recessive autosomal recessive hyper-IgM syndrome type 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0011735
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0011735
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; BMT has been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CD40 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001250.6. 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 | 1 | 1 | 89 | 1 | 92 | |
| missense | 1 | 3 | 61 | 4 | 1 | 70 |
| nonsense | 3 | 3 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 2 | 2 | 4 | |||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 5 | 9 | ||
| Total | 8 | 9 | 67 | 93 | 2 | 179 |
Highest pathogenic variant AF is 0.000013146478
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001241.1 | 9 | MANE Select | |
| Ensembl | ENSP00000361359.3 | 9 | MANE Select | |
| RefSeq | NP_001289682.1 | 8 | Standard | |
| RefSeq | NP_001309350.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Primary immunodeficiency - Homo sapiens (human)
- Cell adhesion molecules (CAMs) - Homo sapiens (human)
- Allograft rejection - Homo sapiens (human)
- Viral myocarditis - Homo sapiens (human)
- Systemic lupus erythematosus - Homo sapiens (human)
Biological Process
- positive regulation of protein phosphorylation
- immune response-regulating cell surface receptor signaling pathway
- cellular calcium ion homeostasis
- inflammatory response
- platelet activation
Molecular Function
- antigen binding
- protein binding
- enzyme binding
- protein domain specific binding
- ubiquitin protein ligase binding
Cellular Component
- cytoplasm
- plasma membrane
- integral component of plasma membrane
- external side of plasma membrane
- cell surface
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000372285
- Coding exons
- 9
- Length
- 11592
- Individuals with no LoFs
- 125745
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125748
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.41 | 104 | 153 | 0.680 | 0.00000850 | 1807 |
| Missense (PolyPhen) | 17 | 46.428 | 0.36616 | 539 | ||
| Synonymous | -0.610 | 66 | 60.0 | 1.10 | 0.00000374 | 517 |
| Loss of Function | 3.10 | 2 | 14.9 | 0.134 | 6.51e-7 | 171 |
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) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor for TNFSF5/CD40LG. Transduces TRAF6- and MAP3K8-mediated signals that activate ERK in macrophages and B cells, leading to induction of immunoglobulin secretion.;
Recessive Scores
- pRec
- 0.728
Intolerance Scores
- LoFtool
- 0.148
- RVIS EVS
- 0.33
- RVIS percentile EVS
- 73.27
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.712
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |