CCND2
protein-codingcyclin D2, the group of Cyclins
Gene summary
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with CDK4 or CDK6 and functions as a regulatory subunit of the complex, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with and be involved in the phosphorylation of tumor suppressor protein Rb. Knockout studies of the homologous gene in mouse suggest the essential roles of this gene in ovarian granulosa and germ cell proliferation. High level expression of this gene was observed in ovarian and testicular tumors. Mutations in this gene are associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 (MPPH3). [provided by RefSeq, Sep 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~35.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014408
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0019375
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014408
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014408
Submitter: ClinGen
CCND2 (Cyclin D2) was first reported in relation to autosomal dominant Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus syndrome in 2014 (Mirzaa et al., PMID: 24705253). CCND2 is a gene that encodes for a protein that functions in the regulation of CDK kinases in the cell cycle and is regulated by the PI3K-AKT pathway. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found evidence in molecular mechanism and phenotypic variability, therefore the following disease entities have been split into two disease entities, microcephaly, short stature & developmental delay and Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) 3 (OMIM 615938). The split curation for microcephaly, short stature & developmental delay will be discussed separately. 9 variants (8 missense, 1 nonsense), that have been reported in 17 probands in 7 publications (PMIDs: 24705253, 31056854,28941273, 29642246, 33634562, 24705253) are included in this curation. More evidence is available in the literature (PMIDs:38700464, 31957131, 32371413, 33144682, 37486637, 36939041), however the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is gain of function. Specifically, mutations in the PEST motif of exon 5 lead to decreased protein degradation and increased protein stability. (PMID: 24705253). The Mouse Genome Informatics (MGI) database lists several CCND2 mutations and alleles; however, none of the corresponding mouse strains met the criteria to be considered non-human model organisms supporting a gene-disease relationship for CCND2. In summary, there is definitive evidence supporting the relationship between CCDN2 and autosomal dominant megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen Brain Malformations GCEP on the meeting date May 27th, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0014408
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014408
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; 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 CCND2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001759.4. 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 | 5 | 25 | 1 | 31 | ||
| missense | 3 | 6 | 70 | 9 | 88 | |
| nonsense | 4 | 3 | 2 | 9 | ||
| start loss | 0 | |||||
| frameshift | 1 | 2 | 1 | 4 | ||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 8 | 11 | 81 | 34 | 1 | 135 |
Highest pathogenic variant AF is 0.000006571252
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001750.1 | 5 | MANE Select | |
| Ensembl | ENSP00000261254.3 | 5 | MANE Select | |
| Ensembl | ENSP00000502508.1 | 6 | Standard | |
| Ensembl | ENSP00000502508.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Focal adhesion - Homo sapiens (human)
- Cell cycle - Homo sapiens (human)
- Jak-STAT signaling pathway - Homo sapiens (human)
- p53 signaling pathway - Homo sapiens (human)
Biological Process
- regulation of cyclin-dependent protein serine/threonine kinase activity
- mitotic cell cycle
- positive regulation of protein phosphorylation
- protein phosphorylation
- regulation of mitotic nuclear division
Molecular Function
- protein kinase activity
- protein binding
- cyclin-dependent protein serine/threonine kinase regulator activity
- protein kinase binding
Cellular Component
- cyclin-dependent protein kinase holoenzyme complex
- chromatin
- nucleus
- nucleoplasm
- nucleolus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000261254
- Coding exons
- 5
- Length
- 31579
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.13 | 91 | 169 | 0.538 | 0.00000888 | 1875 |
| Missense (PolyPhen) | 19 | 60.381 | 0.31467 | 716 | ||
| Synonymous | 0.780 | 67 | 75.6 | 0.886 | 0.00000436 | 582 |
| Loss of Function | 3.35 | 0 | 13.0 | 0.00 | 5.61e-7 | 148 |
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 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Regulatory component of the cyclin D2-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complex and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also substrate for SMAD3, phosphorylating SMAD3 in a cell-cycle-dependent manner and repressing its transcriptional activity. Component of the ternary complex, cyclin D2/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex (By similarity). {ECO:0000250}.;
- Disease
- DISEASE: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 (MPPH3) [MIM:615938]: A syndrome characterized by megalencephaly, ventriculomegaly that may lead to hydrocephalus, and polymicrogyria; polydactyly may also be seen. There is considerable phenotypic similarity between this disorder and the megalencephaly-capillary malformation syndrome. {ECO:0000269|PubMed:24705253}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.750
Intolerance Scores
- LoFtool
- 0.107
- RVIS EVS
- -0.19
- RVIS percentile EVS
- 39.68
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- H
- Indispensability pred.
- E
- Indispensability score
- 0.822
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |