LCK

LCK proto-oncogene, Src family tyrosine kinase, the group of SH2 domain containing|Src family tyrosine kinases

Basic information

Region (hg38): 1:32251244-32286165

Links

ENSG00000182866 ∙ NCBI:3932 ∙ OMIM:153390 ∙ HGNC:6524 ∙ Uniprot:P06239 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• severe combined immunodeficiency due to LCK deficiency (Limited), mode of inheritance: AR
• severe combined immunodeficiency due to LCK deficiency (Supportive), mode of inheritance: AR
• severe combined immunodeficiency due to LCK deficiency (Strong), mode of inheritance: AR
• severe combined immunodeficiency due to LCK deficiency (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 22	AR	Allergy/Immunology/Infectious	Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial	Allergy/Immunology/Infectious	9664084; 11351273; 22985903

ClinVar

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

• Severe combined immunodeficiency due to LCK deficiency (5 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LCK 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	83	3	87
missense			76	4	2	82
nonsense	2	1				3
start loss						0
frameshift	3	1				4
inframe indel						0
splice donor/acceptor (+/-2bp)		1				1
splice region			4	15	1	20
non coding			1	38	3	42
Total	5	3	78	125	8

Variants in LCK

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

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

Position	Type	Phenotype	Significance	ClinVar
1-32274344-C-G		Severe combined immunodeficiency due to LCK deficiency	Uncertain significance (Aug 31, 2021)
1-32274344-C-T		Severe combined immunodeficiency due to LCK deficiency	Likely benign (Jul 17, 2023)
1-32274359-A-T		Severe combined immunodeficiency due to LCK deficiency	Uncertain significance (Sep 24, 2021)
1-32274378-A-G		Severe combined immunodeficiency due to LCK deficiency	Uncertain significance (Nov 08, 2022)
1-32274413-C-A		Severe combined immunodeficiency due to LCK deficiency	Likely benign (Jan 04, 2019)
1-32274413-C-T		Severe combined immunodeficiency due to LCK deficiency	Likely benign (Feb 10, 2022)
1-32274417-C-T		Severe combined immunodeficiency due to LCK deficiency	Likely benign (Jun 20, 2023)
1-32274419-G-A		Severe combined immunodeficiency due to LCK deficiency	Uncertain significance (Jan 17, 2020)
1-32274428-G-A		Severe combined immunodeficiency due to LCK deficiency	Likely benign (Dec 02, 2020)
1-32274429-G-C		Severe combined immunodeficiency due to LCK deficiency	Uncertain significance (Aug 10, 2023)
1-32274433-C-T		Severe combined immunodeficiency due to LCK deficiency	Uncertain significance (Jul 19, 2022)
1-32274444-G-A		Severe combined immunodeficiency due to LCK deficiency	Likely benign (Nov 27, 2023)
1-32274445-A-G		Severe combined immunodeficiency due to LCK deficiency	Likely benign (Aug 10, 2023)
1-32274453-G-A		Severe combined immunodeficiency due to LCK deficiency	Likely benign (Aug 03, 2023)
1-32274723-C-A		Severe combined immunodeficiency due to LCK deficiency	Likely benign (Apr 11, 2023)
1-32274746-C-T		Severe combined immunodeficiency due to LCK deficiency	Pathogenic (Dec 13, 2021)
1-32274750-A-G		Severe combined immunodeficiency due to LCK deficiency	Uncertain significance (Feb 11, 2022)
1-32274765-G-A		Severe combined immunodeficiency due to LCK deficiency • not specified	Benign (Jan 30, 2024)
1-32274772-A-G		Severe combined immunodeficiency due to LCK deficiency	Likely benign (Jan 14, 2024)
1-32274773-C-G		Severe combined immunodeficiency due to LCK deficiency • not specified	Uncertain significance (Aug 08, 2022)
1-32274784-C-T		Severe combined immunodeficiency due to LCK deficiency	Likely benign (Oct 29, 2019)
1-32274785-G-C		Severe combined immunodeficiency due to LCK deficiency	Uncertain significance (Aug 22, 2022)
1-32274791-T-G		Severe combined immunodeficiency due to LCK deficiency	Uncertain significance (Jul 17, 2023)
1-32274792-C-G		Severe combined immunodeficiency due to LCK deficiency	Benign (Jan 20, 2024)
1-32274802-G-A		Severe combined immunodeficiency due to LCK deficiency	Benign (Feb 06, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LCK	protein_coding	protein_coding	ENST00000336890	12	34927

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.000741	125720	0	2	125722	0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.48	151	328	0.460	0.0000212	3322
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000585	0.0000585
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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);Natural killer cell mediated cytotoxicity - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);NF-kappa B signaling pathway - Homo sapiens (human);Thymic Stromal LymphoPoietin (TSLP) Signaling Pathway;B Cell Receptor Signaling Pathway;T-Cell Receptor and Co-stimulatory Signaling;T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection;Inflammatory Response Pathway;IL-2 Signaling Pathway;Interferon type I signaling pathways;Notch Signaling Pathway;Disease;Signal Transduction;Signaling by Interleukins;DAP12 signaling;DAP12 interactions;the co-stimulatory signal during t-cell activation;il 2 signaling pathway;il-7 signal transduction;lck and fyn tyrosine kinases in initiation of tcr activation;role of mef2d in t-cell apoptosis;activation of csk by camp-dependent protein kinase inhibits signaling through the t cell receptor;t cell receptor signaling pathway;Cytokine Signaling in Immune system;Phosphorylation of CD3 and TCR zeta chains;Generation of second messenger molecules;Host Interactions of HIV factors;HIV Infection;Translocation of ZAP-70 to Immunological synapse;B cell receptor signaling;Downstream TCR signaling;TCR signaling;CD28 dependent PI3K/Akt signaling;CD28 dependent Vav1 pathway;CD28 co-stimulation;CTLA4 inhibitory signaling;PD-1 signaling;Costimulation by the CD28 family;CD4 T cell receptor signaling-ERK cascade;TCR;Infectious disease;Innate Immune System;Immune System;Interleukin-2 family signaling;Adaptive Immune System;BCR;GPVI-mediated activation cascade;Platelet activation, signaling and aggregation;IL-7 signaling;Regulation of KIT signaling;Integrin;Nef and signal transduction;EGFR1;SHP2 signaling;PECAM1 interactions;CXCR4-mediated signaling events;Cell surface interactions at the vascular wall;Hemostasis;Thromboxane A2 receptor signaling;PIP3 activates AKT signaling;JAK STAT pathway and regulation;Nef Mediated CD4 Down-regulation;IL2;Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters;The role of Nef in HIV-1 replication and disease pathogenesis;EPO signaling;IL2-mediated signaling events;Ephrin B reverse signaling;Class I PI3K signaling events;PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling;Negative regulation of the PI3K/AKT network;Interleukin-2 signaling;Signaling by SCF-KIT;Constitutive Signaling by Aberrant PI3K in Cancer;PI3K/AKT Signaling in Cancer;Signaling by Receptor Tyrosine Kinases;VEGF;Intracellular signaling by second messengers;IL2 signaling events mediated by STAT5;Diseases of signal transduction;Glypican 1 network;IL2 signaling events mediated by PI3K;TCR signaling in naïve CD8+ T cells;Regulation of p38-alpha and p38-beta;Alpha-synuclein signaling;PDGFR-beta signaling pathway;Signaling events mediated by PTP1B;TCR signaling in naïve CD4+ T cells;IL12-mediated signaling events;Atypical NF-kappaB pathway;EPHA forward signaling;CD4 T cell receptor signaling-JNK cascade;CD4 T cell receptor signaling-NFkB cascade;CD4 T cell receptor signaling (Consensus)

Intolerance Scores

• loftool: 0.128
• rvis_EVS: 0.44
• rvis_percentile_EVS: 77.7

Haploinsufficiency Scores

• pHI: 0.988
• hipred: Y
• hipred_score: 0.809
• ghis: 0.407

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.969

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Lck
• Phenotype: endocrine/exocrine gland phenotype; immune system phenotype; embryo phenotype; reproductive system phenotype; hematopoietic system phenotype

Gene ontology

• 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;peptidyl-tyrosine phosphorylation;hemopoiesis;cell differentiation;platelet activation;T cell differentiation;T cell costimulation;positive regulation of heterotypic cell-cell adhesion;peptidyl-tyrosine autophosphorylation;response to drug;phosphatidylinositol phosphorylation;regulation of defense response to virus by virus;T cell receptor signaling pathway;B cell receptor signaling pathway;positive regulation of T cell receptor signaling pathway;positive regulation of T cell activation;leukocyte migration;release of sequestered calcium ion into cytosol;regulation of lymphocyte activation;positive regulation of protein kinase B signaling;positive regulation of leukocyte cell-cell adhesion;positive regulation of intrinsic apoptotic signaling pathway
• Cellular component: pericentriolar material;immunological synapse;cytosol;plasma membrane;extrinsic component of cytoplasmic side of plasma membrane;membrane raft;extracellular exosome
• Molecular function: phosphotyrosine residue binding;protein tyrosine kinase activity;non-membrane spanning protein tyrosine kinase activity;protein serine/threonine phosphatase activity;signaling receptor binding;protein binding;ATP binding;protein C-terminus binding;kinase activity;protein kinase binding;protein phosphatase binding;SH2 domain binding;T cell receptor binding;CD4 receptor binding;CD8 receptor binding;identical protein binding;phosphatidylinositol 3-kinase binding;phosphatidylinositol-4,5-bisphosphate 3-kinase activity;ATPase binding