ICOS
protein-codinginducible T cell costimulator, the group of CD molecules
Gene summary
The protein encoded by this gene belongs to the CD28 and CTLA-4 cell-surface receptor family. It forms homodimers and plays an important role in cell-cell signaling, immune responses, and regulation of cell proliferation. [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 ~24.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0011864
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0015517
Submitter: ClinGen
The relationship between ICOS and Common variable immunodeficiency (CVID), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of November, 2022. ICOS belongs to the CD28 and CTLA-4 cell-surface receptor family. It forms homodimers and plays an important role in cell-cell signaling, immune responses, and regulation of cell proliferation. ICOS was first reported in relation to autosomal recessive CVID in 2003 (Grimbacher et al, PMID: 12577056). Variants reported in this gene thus far include deletion, frameshift and missense variants. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (12 points): There have been at least 10 patients from 8 publications, till date, reported with homozygous variants in ICOS (PMID: 12577056, 15507387, 26399252, 25678089, 19380800, 28861081, 16384931, 31858365). The mechanism of disease is reported to be biallelic loss of function. Summary of experimental data (5.5 points): This gene-disease association is supported by in-vitro functional assays and animal models. ICOS binds to its ligand, ICOSL, through critical residues (PMID: 11956294). ICOS is shown to interact with PIK3R1 (PMID: 17014982). At least three different mouse models are shown to recapitulate human phenotypes such as hypogammaglobulinemia, Ig class-switch defects, and impaired germinal center reactions, defective antibody response and autoimmunity (PMID: 11343123, 11343122, 11238604, 11343121). Impaired ICOS/ICOSL interactions compromise NK cell activation and NK cell response (PMID: 31283790). In summary, the evidence to support the gene-disease relationship of ICOS and Common variable immunodeficiency is definitive. 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:0011864
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011864
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011864
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: Antiinfectious prophylaxis (including with administration of IVIG) and early and aggressive treatment of infections may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ICOS variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_012092.4. 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 | 42 | 1 | 43 | |||
| missense | 1 | 49 | 3 | 1 | 54 | |
| nonsense | 4 | 1 | 1 | 6 | ||
| start loss | 0 | |||||
| frameshift | 3 | 3 | 6 | |||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 1 | 5 | ||
| Total | 8 | 8 | 51 | 45 | 2 | 114 |
Highest pathogenic variant AF is 0.0000824887
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_036224.1 | 5 | MANE Select | |
| Ensembl | ENSP00000319476.6 | 5 | MANE Select | |
| Ensembl | ENSP00000415951.1 | 4 | Standard | |
| Ensembl | ENSP00000415951.1 | 4 | 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)
- T cell receptor signaling pathway - Homo sapiens (human)
- Intestinal immune network for IgA production - Homo sapiens (human)
- T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection
Biological Process
- T cell tolerance induction
- immune response
- T cell costimulation
- phosphatidylinositol phosphorylation
- positive regulation of protein kinase B signaling
Molecular Function
- protein binding
- phosphatidylinositol-4,5-bisphosphate 3-kinase activity
Cellular Component
- extracellular region
- plasma membrane
- integral component of plasma membrane
- external side of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000316386
- Coding exons
- 5
- Length
- 24830
- Individuals with no LoFs
- 125729
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125731
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.21 | 69 | 104 | 0.666 | 0.00000478 | 1310 |
| Missense (PolyPhen) | 17 | 28.154 | 0.60381 | 392 | ||
| Synonymous | -0.552 | 41 | 36.7 | 1.12 | 0.00000196 | 357 |
| Loss of Function | 1.78 | 4 | 10.1 | 0.395 | 4.25e-7 | 136 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| 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 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Enhances all basic T-cell responses to a foreign antigen, namely proliferation, secretion of lymphokines, up- regulation of molecules that mediate cell-cell interaction, and effective help for antibody secretion by B-cells. Essential both for efficient interaction between T and B-cells and for normal antibody responses to T-cell dependent antigens. Does not up- regulate the production of interleukin-2, but superinduces the synthesis of interleukin-10. Prevents the apoptosis of pre- activated T-cells. Plays a critical role in CD40-mediated class switching of immunoglobin isotypes (By similarity). {ECO:0000250, ECO:0000269|PubMed:11169414, ECO:0000269|PubMed:9930702}.;
- Disease
- DISEASE: Immunodeficiency, common variable, 1 (CVID1) [MIM:607594]: A primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low. {ECO:0000269|PubMed:12577056}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.268
Intolerance Scores
- LoFtool
- 0.428
- RVIS EVS
- 0.26
- RVIS percentile EVS
- 70.06
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.660
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |