CSK
protein-codingC-terminal Src kinase, the group of SH2 domain containing|Csk family tyrosine kinases
Gene summary
The protein encoded by this gene is involved in multiple pathways, including the regulation of Src family kinases. It plays an important role in T-cell activation through its association with the protein encoded by the protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene. This protein also phosphorylates C-terminal tyrosine residues on multiple substrates, including the protein encoded by the SRC proto-oncogene, non-receptor tyrosine kinase gene. Phosphorylation suppresses the kinase activity of the Src family tyrosine kinases. An intronic polymorphism (rs34933034) in this gene has been found to affect B-cell activation and is associated with systemic lupus erythematosus (SLE). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~21.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CSK variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004383.3. 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 | 1 | 5 | |||
| missense | 31 | 1 | 2 | 34 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 0 | 0 | 39 | 2 | 2 | 43 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004374.1 | 12 | MANE Select | |
| Ensembl | ENSP00000220003.9 | 12 | MANE Select | |
| RefSeq | NP_001120662.1 | 12 | Standard | |
| RefSeq | NP_001341917.1 | 12 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| csk | Danio rerio | Structure: whole organism Quality: decreased length abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human)
- VEGF Signaling Pathway
- Integrin-mediated Cell Adhesion
- Integrated Lung Cancer Pathway
- VEGFA-VEGFR2 Signaling Pathway
Biological Process
- adaptive immune response
- protein phosphorylation
- brain development
- negative regulation of cell population proliferation
- negative regulation of low-density lipoprotein particle clearance
Molecular Function
- protein tyrosine kinase activity
- non-membrane spanning protein tyrosine kinase activity
- protein binding
- ATP binding
- protein C-terminus binding
Cellular Component
- cytoplasm
- cytosol
- plasma membrane
- cell-cell junction
- membrane raft
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000220003
- Coding exons
- 12
- Length
- 21142
- Individuals with no LoFs
- 124652
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 124653
- p
- 0.00000401
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.98 | 103 | 295 | 0.349 | 0.0000193 | 2914 |
| Missense (PolyPhen) | 34 | 156.76 | 0.2169 | 1542 | ||
| Synonymous | 0.168 | 124 | 126 | 0.981 | 0.00000917 | 877 |
| Loss of Function | 4.76 | 1 | 28.3 | 0.0353 | 0.00000163 | 293 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| 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 | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Non-receptor tyrosine-protein kinase that plays an important role in the regulation of cell growth, differentiation, migration and immune response. Phosphorylates tyrosine residues located in the C-terminal tails of Src-family kinases (SFKs) including LCK, SRC, HCK, FYN, LYN, CSK or YES1. Upon tail phosphorylation, Src-family members engage in intramolecular interactions between the phosphotyrosine tail and the SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is recruited to the plasma membrane via binding to transmembrane proteins or adapter proteins located near the plasma membrane. Suppresses signaling by various surface receptors, including T- cell receptor (TCR) and B-cell receptor (BCR) by phosphorylating and maintaining inactive several positive effectors such as FYN or LCK. {ECO:0000269|PubMed:1639064, ECO:0000269|PubMed:9281320}.;
Recessive Scores
- pRec
- 0.671
Intolerance Scores
- RVIS EVS
- -0.14
- RVIS percentile EVS
- 43.57
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.989
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |