CCNF
protein-codingcyclin F, the group of Cyclins|MicroRNA protein coding host genes|F-boxes other
Gene summary
This gene encodes a member of the cyclin family. Cyclins are important regulators of cell cycle transitions through their ability to bind and activate cyclin-dependent protein kinases. This member also belongs to the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class and it was one of the first proteins in which the F-box motif was identified. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~29.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0004976
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0004976
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0030875
Submitter: ClinGen
CCNF was first reported in relation to autosomal dominant ALS-FTD in a large family of British ancestry through linkage analysis (Williams et al., 2016, PMID: 27080313). Linkage analysis revealed a candidate region at 16p13.3-p12.3, which was determined to be a novel mutation in CCNF (Ser621Gly) by exome sequencing. CCNF codes for the Cyclin F protein, a component of an E3 ubiquitin–protein ligase (F box protein family) (Skp1-Cul1-F-box) that is involved in mediating the ubiquitination and consequently degradation of target proteins through the ubiquitin proteasome system. At least 37 variants in the CCNF gene have since been reported to cause ALS-FTD in humans of diverse geoancestry across five publications (PMIDs: 27080313, 29102476, 30008669, 28281833, 31475037). However, several reported variants have relatively high minor allele frequencies in population databases (>0.000005) and were not scored as genetic-level evidence. Overall evidence supporting the CCNF gene-disease relationship includes case-level data and experimental data. Mutant Cyclin F (Ser621Gly) has been shown to disrupt Lys48-specific ubiquitylation, resulting in accumulation of RRM2 and TDP43 (PMID: 28852778). The mutant protein interacts with p62/SQSTM1 and leads to defects in autophagic degradation (PMID: 28852778). Additionally, mutant Cyclin F has been shown to cause cytoplasmic mislocalization of Cyclin F and elevated VCP ATPase activity (which promotes cytoplasmic aggregation of TDP-43) (PMID: 31577344). Finally, mutant Cyclin F (Ser621Gly) has been shown to cause disruption of axonal outgrowth, increased cell death in the spinal cord, and aberrant motor phenotype in Zebrafish (PMID: 28444311). In summary, due to limited scorable genetic-level evidence and lack of a strong model system to demonstrate the phenotype of mutant CCNF, there is currently limited evidence to support a gene-disease relationship between CCNF and ALS-FTD. This classification was approved by the ClinGen ALS GCEP on February 8, 2022 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0030875
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CCNF variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001761.3. 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 | 1 | 25 | 2 | 28 | ||
| missense | 2 | 1 | 114 | 20 | 4 | 141 |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 2 | 1 | 121 | 45 | 6 | 175 |
Highest pathogenic variant AF is 0.0000343805
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001752.2 | 17 | MANE Select | |
| Ensembl | ENSP00000380256.4 | 17 | MANE Select | |
| RefSeq | NP_001310467.1 | 9 | Standard | |
| Ensembl | ENSP00000293968.7 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Post-translational protein modification
- Metabolism of proteins
- Immune System
- Adaptive Immune System
- Antigen processing: Ubiquitination & Proteasome degradation
Biological Process
- regulation of cyclin-dependent protein serine/threonine kinase activity
- protein polyubiquitination
- mitotic cell cycle
- re-entry into mitotic cell cycle
- placenta development
Molecular Function
- protein kinase activity
- ubiquitin-protein transferase activity
- protein binding
- cyclin-dependent protein serine/threonine kinase regulator activity
- protein kinase binding
Cellular Component
- cyclin-dependent protein kinase holoenzyme complex
- nucleus
- cytoplasm
- centrosome
- centriole
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000397066
- Coding exons
- 17
- Length
- 29461
- Individuals with no LoFs
- 125729
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 19
- Defined
- 125748
- p
- 0.0000756
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.741 | 424 | 469 | 0.904 | 0.0000286 | 5084 |
| Missense (PolyPhen) | 101 | 144.6 | 0.69847 | 1540 | ||
| Synonymous | 0.433 | 203 | 211 | 0.962 | 0.0000142 | 1572 |
| Loss of Function | 4.44 | 10 | 40.5 | 0.247 | 0.00000222 | 427 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000089 | 0.000088 | rare |
| South Asian | 0.000099 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Substrate recognition component of a SCF (SKP1-CUL1-F- box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of CP110 during G2 phase, thereby acting as an inhibitor of centrosome reduplication. {ECO:0000269|PubMed:20596027}.;
Recessive Scores
- pRec
- 0.131
Intolerance Scores
- LoFtool
- 0.488
- RVIS EVS
- -1.22
- RVIS percentile EVS
- 5.67
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.869
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |