CDC6
protein-codingcell division cycle 6
Gene summary
The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Cdc6, a protein essential for the initiation of DNA replication. This protein functions as a regulator at the early steps of DNA replication. It localizes in cell nucleus during cell cyle G1, but translocates to the cytoplasm at the start of S phase. The subcellular translocation of this protein during cell cyle is regulated through its phosphorylation by Cdks. Transcription of this protein was reported to be regulated in response to mitogenic signals through transcriptional control mechanism involving E2F proteins. [provided by RefSeq, Jul 2008]
- CDC18L
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~16.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013432
Submitter: G2P
Inheritance Pattern: Unknown
Disease ID:MONDO:0013432
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013432
Submitter: ClinGen
*CDC6* was first reported in relation to autosomal recessive Meier-Gorlin Syndrome 5 in 2011 (Bicknell et al. 2011, PMID: 21358632). At least 3 variants (2 missense, one nonsense) have been reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Meier-Gorlin Syndrome 5 is the only disease entity that *CDC6* is associated with.The mechanism of pathogenicity is reported to be loss of function and variants in this gene that have been reported in at least 2 probands in at least 2 publications (PMIDs: 21358632, 35023948) are included in this curation. This gene-disease relationship is also supported by functional alteration in patient cells (PMID: 23516378). CDC6 also has a similar biochemical function to ORC1 and ORC6 (PMID: 23516378). CDC6 is part of the origin recognition complex (ORC); it interacts with ORC1, ORC4, ORC6, CDT1 (PMID: 11477602). Additionally support for this gene-disease relationship comes from an animal model (zebrafish; PMID: 28985365). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date January 17th, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0016817
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013432
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; 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 CDC6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001254.4. 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 | 4 | 44 | 2 | 50 | ||
| missense | 133 | 6 | 2 | 141 | ||
| nonsense | 1 | 5 | 6 | |||
| start loss | 0 | |||||
| frameshift | 7 | 7 | ||||
| splice donor/acceptor (+/-2bp) | 7 | 7 | ||||
| Total | 0 | 1 | 156 | 50 | 4 | 211 |
Highest pathogenic variant AF is 0.000083012026
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001245.1 | 11 | MANE Select | |
| Ensembl | ENSP00000209728.4 | 11 | MANE Select | |
| Ensembl | ENSP00000464047.1 | 2 | Standard | |
| Ensembl | ENSP00000463004.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell cycle - Homo sapiens (human)
- Cell Cycle
- Mitotic G1-G1-S phases
- DNA Replication
- cdk regulation of dna replication
Biological Process
- DNA replication checkpoint
- regulation of cyclin-dependent protein serine/threonine kinase activity
- G1/S transition of mitotic cell cycle
- regulation of transcription involved in G1/S transition of mitotic cell cycle
- mitotic cell cycle
Molecular Function
- nucleotide binding
- DNA replication origin binding
- protein binding
- ATP binding
- kinase binding
Cellular Component
- spindle pole
- nucleus
- nucleoplasm
- nucleolus
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000209728
- Coding exons
- 11
- Length
- 15287
- Individuals with no LoFs
- 125674
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 74
- Defined
- 125748
- p
- 0.000294
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.606 | 255 | 284 | 0.899 | 0.0000145 | 3645 |
| Missense (PolyPhen) | 66 | 87.84 | 0.75137 | 1125 | ||
| Synonymous | 0.542 | 96 | 103 | 0.932 | 0.00000492 | 1104 |
| Loss of Function | 1.54 | 18 | 26.6 | 0.677 | 0.00000140 | 341 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00020 | 0.00020 | rare |
| Ashkenazi Jewish | 0.0013 | 0.0013 | notable |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00037 | 0.00037 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in the initiation of DNA replication. Also participates in checkpoint controls that ensure DNA replication is completed before mitosis is initiated.;
- Disease
- DISEASE: Meier-Gorlin syndrome 5 (MGORS5) [MIM:613805]: A syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal. {ECO:0000269|PubMed:21358632}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.175
Intolerance Scores
- LoFtool
- 0.769
- RVIS EVS
- 0.26
- RVIS percentile EVS
- 70.44
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- N
- Indispensability score
- 0.404
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |