CISH
protein-codingcytokine inducible SH2 containing protein, the group of Suppressors of cytokine signaling|SH2 domain containing
Gene summary
The protein encoded by this gene contains a SH2 domain and a SOCS box domain. The protein thus belongs to the cytokine-induced STAT inhibitor (CIS), also known as suppressor of cytokine signaling (SOCS) or STAT-induced STAT inhibitor (SSI), protein family. CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling. The expression of this gene can be induced by IL2, IL3, GM-CSF and EPO in hematopoietic cells. Proteasome-mediated degradation of this protein has been shown to be involved in the inactivation of the erythropoietin receptor. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~5.3 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 CISH variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_145071.4. 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 | 1 | 3 | |||
| missense | 27 | 3 | 30 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 28 | 5 | 1 | 34 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_659508.1 | 3 | MANE Select | |
| Ensembl | ENSP00000294173.3 | 3 | MANE Select | |
| RefSeq | NP_037456.5 | 3 | Standard | |
| Ensembl | ENSP00000409346.2 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cish | Danio rerio | Structure: myeloid cell Quality: increased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Jak-STAT signaling pathway - Homo sapiens (human)
- Prolactin signaling pathway - Homo sapiens (human)
- JAK-STAT-Ncore
- Regulation of toll-like receptor signaling pathway
- MicroRNAs in cardiomyocyte hypertrophy
Biological Process
- regulation of cell growth
- protein kinase C-activating G protein-coupled receptor signaling pathway
- protein ubiquitination
- intracellular signal transduction
- interleukin-7-mediated signaling pathway
Molecular Function
- molecular_function
- protein binding
- 1-phosphatidylinositol-3-kinase regulator activity
Cellular Component
- cellular_component
- cytosol
- plasma membrane
- phosphatidylinositol 3-kinase complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000443053
- Coding exons
- 3
- Length
- 5342
- Individuals with no LoFs
- 125698
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 18
- Defined
- 125716
- p
- 0.0000716
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.889 | 147 | 181 | 0.814 | 0.0000117 | 1762 |
| Missense (PolyPhen) | 41 | 64.252 | 0.63811 | 628 | ||
| Synonymous | 0.800 | 63 | 71.6 | 0.880 | 0.00000431 | 599 |
| Loss of Function | 0.870 | 6 | 8.78 | 0.683 | 5.45e-7 | 87 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| 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) | 0.000090 | 0.000088 | rare |
| South Asian | 0.00010 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. CIS is involved in the negative regulation of cytokines that signal through the JAK-STAT5 pathway such as erythropoietin, prolactin and interleukin 3 (IL3) receptor. Inhibits STAT5 trans-activation by suppressing its tyrosine phosphorylation. May be a substrate- recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS- box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (By similarity). {ECO:0000250}.;
Recessive Scores
- pRec
- 0.117
Intolerance Scores
- LoFtool
- 0.353
- RVIS EVS
- -0.49
- RVIS percentile EVS
- 22.36
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 |