CD40LG

CD40 ligand, the group of CD molecules|Tumor necrosis factor superfamily

Basic information

Region (hg38): X:136648157-136660390

Previous symbols: [ "HIGM1", "IMD3", "TNFSF5" ]

Links

ENSG00000102245 ∙ NCBI:959 ∙ OMIM:300386 ∙ HGNC:11935 ∙ Uniprot:P29965 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hyper-IgM syndrome type 1 (Definitive), mode of inheritance: XL
• hyper-IgM syndrome type 1 (Supportive), mode of inheritance: XL
• hyper-IgM syndrome type 1 (Strong), mode of inheritance: XL
• hyper-IgM syndrome type 1 (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency, with hyper-IgM, type 1	XL	Allergy/Immunology/Infectious; Oncologic	Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Individuals have been described as being at increased risk of malignancy, and awareness may allow early detection and management; BMT has been reported	Allergy/Immunology/Infectious; Hematologic; Oncologic	7679801; 7678782; 7542361; 9255191; 10228294; 10931436; 10655530; 17296845; 20301576; 23010537; 22322937

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CD40LG gene.

• Hyper-IgM syndrome type 1 (178 variants)
• not provided (41 variants)
• not specified (11 variants)
• Inborn genetic diseases (4 variants)
• Hyperimmunoglobulin M syndrome (2 variants)
• Common variable immunodeficiency (2 variants)
• - (2 variants)
• Immunodeficiency, X-linked, with hyper-IgM (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CD40LG 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			1	15	13	29
missense	9	18	44	2	8	81
nonsense	18	2				20
start loss						0
frameshift	19	6				25
inframe indel			2			2
splice donor/acceptor (+/-2bp)	11	1	1			13
splice region		1	3	2		6
non coding			1	16	7	24
Total	57	27	49	33	28

Highest pathogenic variant AF is 0.00000895

Variants in CD40LG

This is a list of pathogenic ClinVar variants found in the CD40LG region.

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

Position	Type	Phenotype	Significance	ClinVar
X-136648243-C-T		CD40LG-related disorder	Likely benign (May 21, 2019)
X-136648254-C-T		Hyper-IgM syndrome type 1	Benign (Jan 14, 2024)
X-136648255-G-A		Hyper-IgM syndrome type 1	Uncertain significance (Mar 07, 2020)
X-136648263-C-A		Hyper-IgM syndrome type 1	Pathogenic (Aug 23, 2022)
X-136648274-C-T		Hyper-IgM syndrome type 1	Uncertain significance (Dec 15, 2019)
X-136648278-C-G		Hyper-IgM syndrome type 1	Benign (Nov 04, 2023)
X-136648279-C-T		Hyper-IgM syndrome type 1 • not specified	Pathogenic (May 09, 2023)
X-136648280-G-A		Hyper-IgM syndrome type 1	Benign/Likely benign (Jan 27, 2024)
X-136648286-C-A		Hyper-IgM syndrome type 1	Uncertain significance (Sep 16, 2022)
X-136648286-C-T		not specified • Hyper-IgM syndrome type 1	Conflicting classifications of pathogenicity (Nov 13, 2023)
X-136648287-G-A		Hyper-IgM syndrome type 1	Benign (Jan 31, 2024)
X-136648290-CA-C		Hyper-IgM syndrome type 1	Pathogenic (May 20, 2022)
X-136648297-C-G		Hyper-IgM syndrome type 1	Uncertain significance (Feb 18, 2020)
X-136648304-T-G		Inborn genetic diseases	Uncertain significance (Jan 23, 2023)
X-136648308-C-G		Hyper-IgM syndrome type 1	Uncertain significance (Mar 08, 2023)
X-136648321-A-G		Hyper-IgM syndrome type 1	Uncertain significance (Feb 18, 2020)
X-136648329-A-G		Hyper-IgM syndrome type 1	Benign (Jan 29, 2024)
X-136648346-T-A		Common variable immunodeficiency	Uncertain significance (Jan 01, 2019)
X-136648355-T-A		Hyper-IgM syndrome type 1	Conflicting classifications of pathogenicity (Oct 12, 2020)
X-136648355-T-C		Hyper-IgM syndrome type 1	Uncertain significance (Apr 16, 2021)
X-136648355-T-G		Hyper-IgM syndrome type 1	Pathogenic/Likely pathogenic (Feb 11, 2022)
X-136648356-G-A		Hyper-IgM syndrome type 1	Uncertain significance (Feb 03, 2019)
X-136648356-GATTGGGTCAGCACTTTTTGCTGTGTATCTTC-G		Hyper-IgM syndrome type 1	Pathogenic (Dec 08, 2022)
X-136648362-G-A		Hyper-IgM syndrome type 1	Benign (Aug 20, 2021)
X-136648370-T-C		Hyper-IgM syndrome type 1	Uncertain significance (Mar 17, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CD40LG	protein_coding	protein_coding	ENST00000370629	5	12198

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.721	0.277	124699	0	2	124701	0.00000802

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.30	61	97.1	0.628	0.00000715	1730
Missense in Polyphen		7	23.349	0.2998		433
Synonymous	1.03	32	40.3	0.794	0.00000347	480
Loss of Function	2.39	1	8.52	0.117	6.12e-7	152

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000247	0.0000178
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Cytokine that binds to CD40/TNFRSF5 (PubMed:1280226). Costimulates T-cell proliferation and cytokine production. Its cross-linking on T-cells generates a costimulatory signal which enhances the production of IL4 and IL10 in conjunction with the TCR/CD3 ligation and CD28 costimulation (PubMed:8617933). Induces the activation of NF-kappa-B and kinases MAPK8 and PAK2 in T- cells. Induces tyrosine phosphorylation of isoform 3 of CD28 (PubMed:15067037). Mediates B-cell proliferation in the absence of co-stimulus as well as IgE production in the presence of IL4. Involved in immunoglobulin class switching (By similarity). {ECO:0000250|UniProtKB:P27548, ECO:0000269|PubMed:1280226, ECO:0000269|PubMed:15067037, ECO:0000269|PubMed:8617933}.
• Disease: DISEASE: Immunodeficiency with hyper-IgM, type 1 (HIGM1) [MIM:308230]: Immunoglobulin isotype switch defect characterized by elevated concentrations of serum IgM and decreased amounts of all other isotypes. Affected males present at an early age (usually within the first year of life) recurrent bacterial and opportunistic infections, including Pneumocystis carinii pneumonia and intractable diarrhea due to cryptosporidium infection. Despite substitution treatment with intravenous immunoglobulin, the overall prognosis is rather poor, with a death rate of about 10% before adolescence. {ECO:0000269|PubMed:26545377, ECO:0000269|PubMed:7532185, ECO:0000269|PubMed:7678782, ECO:0000269|PubMed:7679206, ECO:0000269|PubMed:7679801, ECO:0000269|PubMed:7717401, ECO:0000269|PubMed:8094231, ECO:0000269|PubMed:8550833, ECO:0000269|PubMed:8889581, ECO:0000269|PubMed:9150729, ECO:0000269|PubMed:9746782}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Primary immunodeficiency - Homo sapiens (human);Cell adhesion molecules (CAMs) - Homo sapiens (human);T cell receptor signaling pathway - Homo sapiens (human);Allograft rejection - Homo sapiens (human);Viral myocarditis - Homo sapiens (human);Systemic lupus erythematosus - Homo sapiens (human);Autoimmune thyroid disease - Homo sapiens (human);Asthma - Homo sapiens (human);Malaria - Homo sapiens (human);Toxoplasmosis - Homo sapiens (human);NF-kappa B signaling pathway - Homo sapiens (human);Cytokine-cytokine receptor interaction - Homo sapiens (human);Intestinal immune network for IgA production - Homo sapiens (human);Allograft Rejection;Photodynamic therapy-induced NF-kB survival signaling;T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection;Inflammatory Response Pathway;cd40l signaling pathway;TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway;TNFR2 non-canonical NF-kB pathway;Cytokine Signaling in Immune system;JAK STAT MolecularVariation 1;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Immune System;Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell;Adaptive Immune System;GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;JAK STAT pathway and regulation;GPCR signaling-G alpha i;CD40/CD40L signaling;Calcineurin-regulated NFAT-dependent transcription in lymphocytes;IL4-mediated signaling events;Calcium signaling in the CD4+ TCR pathway;Beta2 integrin cell surface interactions (Consensus)

Recessive Scores

• pRec: 0.761

Intolerance Scores

• rvis_EVS: -0.03
• rvis_percentile_EVS: 51.4

Haploinsufficiency Scores

• pHI: 0.610
• hipred: Y
• hipred_score: 0.650
• ghis: 0.406

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.642

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cd40lg
• Phenotype: endocrine/exocrine gland 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); cellular phenotype; homeostasis/metabolism 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); 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); 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; skeleton phenotype; renal/urinary system phenotype; immune system phenotype

Gene ontology

• Biological process: inflammatory response;leukocyte cell-cell adhesion;activation of JUN kinase activity;regulation of signaling receptor activity;platelet activation;B cell differentiation;T cell costimulation;positive regulation of interleukin-10 production;positive regulation of interleukin-12 production;positive regulation of interleukin-4 production;tumor necrosis factor-mediated signaling pathway;B cell proliferation;positive regulation of T cell proliferation;negative regulation of apoptotic process;isotype switching;immunoglobulin secretion;regulation of immune response;regulation of immunoglobulin secretion;positive regulation of NF-kappaB transcription factor activity;positive regulation of endothelial cell apoptotic process
• Cellular component: extracellular space;plasma membrane;integral component of plasma membrane;external side of plasma membrane;cell surface;integral component of membrane
• Molecular function: cytokine activity;tumor necrosis factor receptor binding;CD40 receptor binding;protein binding