CLCF1
protein-codingcardiotrophin like cytokine factor 1, the group of Interleukin 6 type cytokine family
Gene summary
This gene is a member of the glycoprotein (gp)130 cytokine family and encodes cardiotrophin-like cytokine factor 1 (CLCF1). CLCF1 forms a heterodimer complex with cytokine receptor-like factor 1 (CRLF1). This dimer competes with ciliary neurotrophic factor (CNTF) for binding to the ciliary neurotrophic factor receptor (CNTFR) complex, and activates the Jak-STAT signaling cascade. CLCF1 can be actively secreted from cells by forming a complex with soluble type I CRLF1 or soluble CNTFR. CLCF1 is a potent neurotrophic factor, B-cell stimulatory agent and neuroendocrine modulator of pituitary corticotroph function. Defects in CLCF1 cause cold-induced sweating syndrome 2 (CISS2). This syndrome is characterized by a profuse sweating after exposure to cold as well as congenital physical abnormalities of the head and spine. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~10.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0015526
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0010091
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012467
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Neurologic
Intervention: Neurologic
Rationale: In the neonatal/early childhood period, the condition can be lethal unless advanced care is instituted; Later, it has been described that cold-induced sweating was alleviated by medical treatment (eg, with clonidine, with lasting effects when co-administered with amitriptyline)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CLCF1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_013246.3. 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 | 12 | 12 | ||||
| missense | 2 | 42 | 3 | 1 | 48 | |
| nonsense | 1 | 1 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 3 | 0 | 44 | 15 | 2 | 64 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_037378.1 | 3 | MANE Select | |
| Ensembl | ENSP00000309338.7 | 3 | MANE Select | |
| RefSeq | NP_001159684.1 | 2 | Standard | |
| Ensembl | ENSP00000434122.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cytokine-cytokine receptor interaction - Homo sapiens (human)
- Signaling by Interleukins
- IL-6-type cytokine receptor ligand interactions
- Cytokine Signaling in Immune system
- Immune System
Biological Process
- positive regulation of immunoglobulin production
- cell surface receptor signaling pathway
- JAK-STAT cascade
- positive regulation of cell population proliferation
- regulation of signaling receptor activity
Molecular Function
- signaling receptor binding
- cytokine activity
- ciliary neurotrophic factor receptor binding
- protein binding
- growth factor activity
Cellular Component
- extracellular region
- CRLF-CLCF1 complex
- CNTFR-CLCF1 complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000312438
- Coding exons
- 3
- Length
- 10010
- Individuals with no LoFs
- 125731
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125735
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.12 | 104 | 141 | 0.735 | 0.00000871 | 1438 |
| Missense (PolyPhen) | 28 | 48.076 | 0.58241 | 526 | ||
| Synonymous | 0.408 | 54 | 58.0 | 0.932 | 0.00000333 | 487 |
| Loss of Function | 2.83 | 0 | 9.32 | 0.00 | 4.86e-7 | 88 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| 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) | 0.000018 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Cytokine with B-cell stimulating capability. Binds to and activates the ILST/gp130 receptor. {ECO:0000269|PubMed:10448081, ECO:0000269|PubMed:10500198}.;
Recessive Scores
- pRec
- 0.248
Intolerance Scores
- LoFtool
- 0.367
- RVIS EVS
- -0.01
- RVIS percentile EVS
- 53.51
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- H
- Indispensability pred.
- E
- Indispensability score
- 0.965
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |