HCK
protein-codingHCK proto-oncogene, Src family tyrosine kinase, the group of Src family tyrosine kinases|SH2 domain containing
Gene summary
The protein encoded by this gene is a member of the Src family of tyrosine kinases. This protein is primarily hemopoietic, particularly in cells of the myeloid and B-lymphoid lineages. It may help couple the Fc receptor to the activation of the respiratory burst. In addition, it may play a role in neutrophil migration and in the degranulation of neutrophils. Multiple isoforms with different subcellular distributions are produced due to both alternative splicing and the use of alternative translation initiation codons, including a non-AUG (CUG) codon. [provided by RefSeq, Feb 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~49.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0957204
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0957204
Submitter: G2P
Inheritance Pattern: Unknown
Disease ID:MONDO:0957204
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Hematologic; Pulmonary
Intervention: Allergy/Immunology/Infectious
Rationale: Individuals may be at risk of infections, and awareness may allow preventative measures and early and aggressive treatment of infections; The condition can involve systemic autoinflammation, and medical management (eg, with JAK inhibitors) has been described as providing some benefit
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HCK variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002110.5. 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 | 3 | 10 | 3 | 16 | ||
| missense | 72 | 11 | 83 | |||
| nonsense | 1 | 1 | 2 | |||
| start loss | 1 | 1 | 2 | |||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 1 | 1 | 77 | 22 | 3 | 104 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002101.2 | 13 | MANE Select | |
| Ensembl | ENSP00000365012.3 | 13 | MANE Select | |
| RefSeq | NP_001165600.1 | 12 | Standard | |
| RefSeq | NP_001165601.1 | 13 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Fc gamma R-mediated phagocytosis - Homo sapiens (human)
- Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
- Chemokine signaling pathway - Homo sapiens (human)
- Thymic Stromal LymphoPoietin (TSLP) Signaling Pathway
- IL-3 Signaling Pathway
Biological Process
- leukocyte migration involved in immune response
- innate immune response-activating signal transduction
- protein phosphorylation
- inflammatory response
- cell adhesion
Molecular Function
- phosphotyrosine residue binding
- protein tyrosine kinase activity
- non-membrane spanning protein tyrosine kinase activity
- signaling receptor binding
- protein binding
Cellular Component
- nucleoplasm
- lysosome
- Golgi apparatus
- cytosol
- actin filament
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000375852
- Coding exons
- 13
- Length
- 49669
- Individuals with no LoFs
- 125718
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 29
- Defined
- 125747
- p
- 0.000115
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.70 | 236 | 322 | 0.733 | 0.0000198 | 3455 |
| Missense (PolyPhen) | 81 | 149.77 | 0.54085 | 1582 | ||
| Synonymous | 1.49 | 106 | 127 | 0.832 | 0.00000843 | 1000 |
| Loss of Function | 3.64 | 9 | 30.8 | 0.292 | 0.00000181 | 327 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00016 | 0.00016 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS. {ECO:0000269|PubMed:10092522, ECO:0000269|PubMed:10779760, ECO:0000269|PubMed:10973280, ECO:0000269|PubMed:11741929, ECO:0000269|PubMed:11896602, ECO:0000269|PubMed:12411494, ECO:0000269|PubMed:15010462, ECO:0000269|PubMed:15952790, ECO:0000269|PubMed:15998323, ECO:0000269|PubMed:17310994, ECO:0000269|PubMed:17535448, ECO:0000269|PubMed:19114024, ECO:0000269|PubMed:19903482, ECO:0000269|PubMed:20452982, ECO:0000269|PubMed:21338576, ECO:0000269|PubMed:7535819, ECO:0000269|PubMed:8132624, ECO:0000269|PubMed:9406996, ECO:0000269|PubMed:9407116}.;
- Disease
- DISEASE: Note=Aberrant activation of HCK by HIV-1 protein Nef enhances HIV-1 replication and contributes to HIV-1 pathogenicity.; DISEASE: Note=Aberrant activation of HCK, e.g. by the BCR-ABL fusion protein, promotes cancer cell proliferation.;
Recessive Scores
- pRec
- 0.532
Intolerance Scores
- LoFtool
- 0.176
- RVIS EVS
- -0.02
- RVIS percentile EVS
- 52.09
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.962
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |