LCK
protein-codingLCK proto-oncogene, Src family tyrosine kinase, the group of SH2 domain containing|Src family tyrosine kinases
Gene summary
This gene is a member of the Src family of protein tyrosine kinases (PTKs). The encoded protein is a key signaling molecule in the selection and maturation of developing T-cells. It contains N-terminal sites for myristylation and palmitylation, a PTK domain, and SH2 and SH3 domains which are involved in mediating protein-protein interactions with phosphotyrosine-containing and proline-rich motifs, respectively. The protein localizes to the plasma membrane and pericentrosomal vesicles, and binds to cell surface receptors, including CD4 and CD8, and other signaling molecules. Multiple alternatively spliced variants encoding different isoforms have been described. [provided by RefSeq, Aug 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~34.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014334
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014334
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014334
Submitter: ClinGen
LCK was first reported in relation to autosomal recessive combined immunodeficiency (CID) due to LCK deficiency in 2012 (Hauck et al., PMID: 22985903). LCK deficiency has been reported in patients with typical symptoms of CID including decreased CD4+ T cells, failure to thrive, recurrent infections, hepatosplenomegaly, intestinal inflammation, and diarrhea. Affected individuals in one family were identified in adulthood with epidermodysplasia verruciformis, T-cell lymphopenia and a history of recurrent chest infections. Heterozygous carriers were reported to be unaffected. Five variants (missense, frameshift, and canonical splice site) that have been reported in five unrelated probands in five publications (PMIDs: 22985903, 38112969, 27087313, 37962568, 38100037) are included in this curation. Variants in this gene segregated with disease in four families. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by mouse model, rescue in cell culture model, expression, protein interaction, and biochemical function studies. LCK expression is restricted to lymphoid tissues and lymphocytes (PMID: 2416464). LCK was significantly reduced in T cells of a patient with CID (PMID: 9664084). LCK co-localizes with the pre-TCR and causes phosphorylation of the ITAMs of the CD3 epsilon, delta, and zeta chains and ZAP70 (PMID: 10952314). LCK activates DNA binding of STAT5A and STAT5B and LCK-deficient T-cells do not have activated STAT5 (PMID: 9880255). LCK-deficient T-cells have altered intracellular Ca2+ mobilization and tyrosine phosphorylation and expression of WT LCK restores TCR-mediated Ca2+ flux and tyrosine phosphorylation signals (PMID: 22985903). Mice with absent LCK had thymic atrophy, dramatically reduced double-positive (CD4+CD8+) thymocyte population, no detectable mature single-positive thymocytes, and very few peripheral T cells (PMID: 1579166). A hypomorphic phenotype with T-cell lymphopenia and survival to adulthood has also been reported (PMID: 27087313). This gene-disease pair was originally evaluated by the SCID-CID GCEP on 7/15/2022. It was reevaluated on 07/17/2025. As a result of this reevaluation, the classification changed from moderate to definitive with the addition of new case-level genetic evidence (PMID: 38112969, 37962568, 38100037).
Inheritance Pattern: AR
Disease ID:MONDO:0014334
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014334
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to LCK variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005356.5. 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 | 2 | 114 | 1 | 117 | ||
| missense | 3 | 106 | 6 | 115 | ||
| nonsense | 2 | 2 | 1 | 5 | ||
| start loss | 0 | |||||
| frameshift | 3 | 2 | 1 | 6 | ||
| splice donor/acceptor (+/-2bp) | 1 | 5 | 1 | 7 | ||
| Total | 9 | 9 | 109 | 122 | 1 | 250 |
Highest pathogenic variant AF is 0.0007811906
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005347.3 | 12 | MANE Select | |
| Ensembl | ENSP00000337825.5 | 12 | MANE Select | |
| RefSeq | NP_001036236.1 | 12 | Standard | |
| RefSeq | NP_001317397.1 | 11 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Primary immunodeficiency - Homo sapiens (human)
- T cell receptor signaling pathway - Homo sapiens (human)
- HTLV-I infection - Homo sapiens (human)
- Th17 cell differentiation - Homo sapiens (human)
- Th1 and Th2 cell differentiation - Homo sapiens (human)
Biological Process
- protein phosphorylation
- protein dephosphorylation
- cellular zinc ion homeostasis
- activation of cysteine-type endopeptidase activity involved in apoptotic process
- transmembrane receptor protein tyrosine kinase signaling pathway
Molecular Function
- phosphotyrosine residue binding
- protein tyrosine kinase activity
- non-membrane spanning protein tyrosine kinase activity
- protein serine/threonine phosphatase activity
- signaling receptor binding
Cellular Component
- pericentriolar material
- immunological synapse
- cytosol
- plasma membrane
- extrinsic component of cytoplasmic side of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000336890
- Coding exons
- 12
- Length
- 34927
- Individuals with no LoFs
- 125720
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125722
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.48 | 151 | 328 | 0.460 | 0.0000212 | 3322 |
| Missense (PolyPhen) | 53 | 150.63 | 0.35185 | 1458 | ||
| Synonymous | 1.02 | 123 | 138 | 0.889 | 0.00000946 | 990 |
| Loss of Function | 4.70 | 2 | 29.6 | 0.0675 | 0.00000158 | 304 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T- cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP. Interacts with FYB2 (PubMed:27335501). {ECO:0000269|PubMed:16339550, ECO:0000269|PubMed:16709819, ECO:0000269|PubMed:20028775, ECO:0000269|PubMed:20100835, ECO:0000269|PubMed:20851766, ECO:0000269|PubMed:21269457, ECO:0000269|PubMed:22080863, ECO:0000269|PubMed:27335501}.;
- Disease
- DISEASE: Note=A chromosomal aberration involving LCK is found in leukemias. Translocation t(1;7)(p34;q34) with TCRB.; DISEASE: Immunodeficiency 22 (IMD22) [MIM:615758]: A primary immunodeficiency characterized by T-cell dysfunction. Affected individuals present with lymphopenia, recurrent infections, severe diarrhea, and failure to thrive. {ECO:0000269|PubMed:22985903}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.128
- RVIS EVS
- 0.44
- RVIS percentile EVS
- 77.7
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.969
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |