ITK
protein-codingIL2 inducible T cell kinase, the group of Tec family tyrosine kinases|SH2 domain containing|Pleckstrin homology domain containing
Gene summary
This gene encodes an intracellular tyrosine kinase expressed in T-cells. The protein contains both SH2 and SH3 domains which are often found in intracellular kinases. It is thought to play a role in T-cell proliferation and differentiation. [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 ~112.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013081
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0016537
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013081
Submitter: ClinGen
There is sufficient evidence published associating the ITK gene with lymphoproliferative syndrome 1 since the gene-disease relationship was firstly proposed by Huck et al (2009). Multiple studies of case level have been performed with patients with lymphoproliferative syndrome 1 that have biallelic loss of function variants in the ITK gene. ITK-/- mouse model has been established to recap partial patients’ phenotypes including decreased number of natural killer T cells. Lymph nodes from patients were found with significantly decreased ITK immunoreactivity compared with normal controls. All of these evidence suggest a definitive relationship between the ITK gene and lymphoproliferative syndrome 1.
Inheritance Pattern: AR
Disease ID:MONDO:0013081
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013081
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Oncologic
Intervention: Allergy/Immunology/Infectious; Oncologic
Rationale: Due to the risk of malignancy, surveillance may allow prompt treatment; Medical treatment (eg, chemotherapy, virostatic agents, corticosteroids, rituximab) may induce remission, but treatment with HSCT may be required; Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial
Comments: Individuals may also have related predisposition to infectious complications
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ITK variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005546.4. 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 | 4 | 145 | 149 | |||
| missense | 2 | 231 | 10 | 243 | ||
| nonsense | 10 | 1 | 11 | |||
| start loss | 1 | 1 | ||||
| frameshift | 5 | 2 | 7 | |||
| splice donor/acceptor (+/-2bp) | 3 | 4 | 7 | |||
| Total | 15 | 8 | 240 | 155 | 0 | 418 |
Highest pathogenic variant AF is 0.000011153301
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005537.3 | 17 | MANE Select | |
| Ensembl | ENSP00000398655.4 | 17 | MANE Select | |
| Ensembl | ENSP00000431054.1 | 4 | Standard | |
| Ensembl | ENSP00000430327.1 | 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)
- Chemokine signaling pathway - Homo sapiens (human)
- Leukocyte transendothelial migration - Homo sapiens (human)
- T-Cell Receptor and Co-stimulatory Signaling
- T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection
Biological Process
- cytokine production
- NK T cell differentiation
- adaptive immune response
- cellular defense response
- signal transduction
Molecular Function
- non-membrane spanning protein tyrosine kinase activity
- protein binding
- ATP binding
- metal ion binding
Cellular Component
- nucleus
- cytosol
- cell-cell junction
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000422843
- Coding exons
- 17
- Length
- 112258
- Individuals with no LoFs
- 125722
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 26
- Defined
- 125748
- p
- 0.000103
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.53 | 253 | 331 | 0.764 | 0.0000197 | 4072 |
| Missense (PolyPhen) | 76 | 138.65 | 0.54813 | 1682 | ||
| Synonymous | -2.04 | 151 | 122 | 1.24 | 0.00000697 | 1153 |
| Loss of Function | 2.98 | 19 | 39.1 | 0.485 | 0.00000223 | 450 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00013 | 0.00013 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation (PubMed:12186560, PubMed:12682224, PubMed:21725281). Phosphorylates TBX21 at 'Tyr-530' and mediates its interaction with GATA3 (By similarity). {ECO:0000250|UniProtKB:Q03526, ECO:0000269|PubMed:12186560, ECO:0000269|PubMed:12682224, ECO:0000269|PubMed:21725281}.;
- Disease
- DISEASE: Lymphoproliferative syndrome 1 (LPFS1) [MIM:613011]: A rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Inadequate immune response to EBV can have a fatal outcome. Clinical features include splenomegaly, lymphadenopathy, anemia, thrombocytopenia, pancytopenia, recurrent infections. There is an increased risk for lymphoma. {ECO:0000269|PubMed:19425169}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.367
Intolerance Scores
- LoFtool
- 0.261
- RVIS EVS
- -0.22
- RVIS percentile EVS
- 37.43
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.767
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |