ITK

IL2 inducible T cell kinase, the group of Tec family tyrosine kinases|SH2 domain containing|Pleckstrin homology domain containing

Basic information

Region (hg38): 5:157142932-157255185

Links

ENSG00000113263 ∙ NCBI:3702 ∙ OMIM:186973 ∙ HGNC:6171 ∙ Uniprot:Q08881 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• lymphoproliferative syndrome 1 (Strong), mode of inheritance: AR
• lymphoproliferative syndrome 1 (Moderate), mode of inheritance: AR
• lymphoproliferative syndrome 1 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Lymphoproliferative syndrome 1	AR	Allergy/Immunology/Infectious; Oncologic	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	Allergy/Immunology/Infectious; Oncologic	19425169; 21109689; 22289921; 22487848
Individuals may also have related predisposition to infectious complications

ClinVar

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

• Lymphoproliferative syndrome 1 (405 variants)
• not provided (33 variants)
• Autoinflammatory syndrome (17 variants)
• Inborn genetic diseases (14 variants)
• not specified (13 variants)
• ITK-related condition (4 variants)
• Lymphoproliferative disorder (2 variants)
• Vitiligo-associated multiple autoimmune disease susceptibility 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ITK 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			4	91	2	97
missense			158	6		164
nonsense	6					6
start loss						0
frameshift	3					3
inframe indel			1			1
splice donor/acceptor (+/-2bp)			2			2
splice region			9	16		25
non coding			38	47	39	124
Total	9	0	203	144	41

Highest pathogenic variant AF is 0.00000657

Variants in ITK

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

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

Position	Type	Phenotype	Significance	ClinVar
5-157162458-T-C		not specified	Uncertain significance (Aug 08, 2023)
5-157162481-G-A		not specified	Likely benign (Jan 03, 2024)
5-157162508-A-G		not specified	Uncertain significance (Dec 15, 2022)
5-157162559-T-G		not specified	Uncertain significance (Apr 13, 2023)
5-157162597-T-G		not specified	Uncertain significance (Feb 06, 2024)
5-157162626-A-G		not specified	Uncertain significance (Feb 21, 2024)
5-157162649-C-T			Likely benign (Apr 01, 2024)
5-157162671-T-A		not specified	Uncertain significance (Dec 12, 2023)
5-157162704-C-G		not specified	Uncertain significance (Aug 01, 2022)
5-157162769-C-A		not specified	Uncertain significance (Jan 23, 2024)
5-157162804-G-T		not specified	Uncertain significance (Oct 19, 2021)
5-157162899-T-C		not specified	Uncertain significance (Aug 01, 2022)
5-157162900-C-G		not specified	Uncertain significance (Oct 04, 2022)
5-157162925-C-A		not specified	Uncertain significance (Jul 19, 2022)
5-157163061-A-C		not specified	Uncertain significance (Dec 08, 2023)
5-157163064-T-C		not specified	Uncertain significance (Feb 26, 2024)
5-157163087-G-T		not specified	Uncertain significance (Oct 02, 2023)
5-157163226-C-T		not specified	Uncertain significance (Dec 18, 2023)
5-157163239-G-T		not specified	Uncertain significance (Apr 25, 2023)
5-157163246-C-A		not specified	Uncertain significance (Nov 09, 2023)
5-157163256-A-T		not specified	Uncertain significance (Oct 06, 2022)
5-157163261-T-C		not specified	Likely benign (Sep 21, 2023)
5-157163273-G-A		not specified	Uncertain significance (Aug 13, 2021)
5-157163354-G-A		not specified	Uncertain significance (Apr 07, 2023)
5-157163403-C-T		not specified	Uncertain significance (Feb 15, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ITK	protein_coding	protein_coding	ENST00000422843	17	112258

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.14e-8	0.999	125722	0	26	125748	0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.53	253	331	0.764	0.0000197	4072
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000148	0.000148
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000132	0.000132
Middle Eastern	0.0000544	0.0000544
South Asian	0.000163	0.000163
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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;Chemokine signaling pathway;T-Cell antigen Receptor (TCR) Signaling Pathway;the co-stimulatory signal during t-cell activation;Generation of second messenger molecules;TCR signaling;CD4 T cell receptor signaling-ERK cascade;FCERI mediated Ca+2 mobilization;Fc epsilon receptor (FCERI) signaling;TCR;Innate Immune System;Immune System;Adaptive Immune System;BCR;IL-7 signaling;JAK STAT pathway and regulation;EPO signaling;Class I PI3K signaling events;VEGF;Fc-epsilon receptor I signaling in mast cells;TCR signaling in naïve CD4+ T cells;CD4 T cell receptor signaling-JNK cascade;CD4 T cell receptor signaling-NFkB cascade;CD4 T cell receptor signaling (Consensus)

Recessive Scores

• pRec: 0.367

Intolerance Scores

• loftool: 0.261
• rvis_EVS: -0.22
• rvis_percentile_EVS: 37.43

Haploinsufficiency Scores

• pHI: 0.568
• hipred: Y
• hipred_score: 0.624
• ghis: 0.511

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.767

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Itk
• Phenotype: immune system phenotype; hematopoietic system phenotype; cellular phenotype; endocrine/exocrine gland phenotype

Gene ontology

• Biological process: cytokine production;NK T cell differentiation;adaptive immune response;cellular defense response;signal transduction;activation of phospholipase C activity;interferon-gamma production;interleukin-4 production;intracellular signal transduction;peptidyl-tyrosine autophosphorylation;Fc-epsilon receptor signaling pathway;T cell activation;T cell receptor signaling pathway;B cell receptor signaling pathway
• Cellular component: nucleus;cytosol;cell-cell junction
• Molecular function: non-membrane spanning protein tyrosine kinase activity;protein binding;ATP binding;metal ion binding