CDKN1C
protein-codingcyclin dependent kinase inhibitor 1C
Gene summary
This gene is imprinted, with preferential expression of the maternal allele. The encoded protein is a tight-binding, strong inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell proliferation. Mutations in this gene are implicated in sporadic cancers and Beckwith-Wiedemann syndorome, suggesting that this gene is a tumor suppressor candidate. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]
- BWCR
- BWS
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~2.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0016476
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013873
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0016476
Submitter: ClinGen
CDKN1C (cyclin dependent kinase inhibitor 1C), also known as P57Kip2, was first reported in relation to autosomal dominant Beckwith‑Wiedemann syndrome (BWS) with parent‑of‑origin effects in 1996 (PMID: 8841187). CDKN1C is located at chromosome 11p15.5 and encodes a cyclin‑dependent kinase inhibitor that plays a key role in regulating cell‑cycle progression and cellular proliferation. CDKN1C is a maternally expressed imprinted gene, with the paternal allele normally silenced. Beckwith‑Wiedemann syndrome is a congenital overgrowth disorder characterized by prenatal and/or postnatal macrosomia, macroglossia, abdominal wall defects (omphalocele, umbilical hernia), visceromegaly, neonatal hypoglycemia, and ear creases or pits. Individuals with Beckwith‑Wiedemann syndrome are also at increased risk for embryonal tumors in childhood, in particular Wilms tumor and hepatoblastoma, consistent with the established clinical spectrum of the condition. Per ClinGen Lumping and Splitting Working Group criteria, disorders associated with CDKN1C were split into separate disease entities. Loss‑of‑function or silencing of the maternally inherited allele causes Beckwith‑Wiedemann syndrome(OMIM:130650), whereas gain‑of‑function variants,typically affecting the PCNA‑binding domain,cause growth‑restriction phenotypes such as IMAGe syndrome(OMIM:614732) or, more rarely, Silver‑Russell syndrome (OMIM:180860). These conditions differ with respect to molecular mechanism, inheritance, and phenotypic presentation and are therefore curated separately. 13 pathogenic variants in CDKN1C have been reported in individuals with Beckwith‑Wiedemann syndrome across independent publications (PMIDs:39502854, 20503313, 11106355, 34065128, and 8841187). The variant spectrum includes nonsense, frameshift, splice‑altering, and deleterious missense variants, consistent with loss of gene function. Pathogenic variants are associated with disease only when maternally inherited, consistent with the imprinted expression of CDKN1C. Segregation of maternally inherited CDKN1C variants with Beckwith‑Wiedemann syndrome has been demonstrated in multiple families, while paternal inheritance does not result in phenotype(PMID: 19550435). More genetic evidence supporting this relationship is available in the literature; however, the maximum score for genetic evidence has been reached. The mechanism of disease is loss of function of the maternally expressed CDKN1C allele, leading to reduced or absent p57Kip2 activity and subsequent dysregulation of cell‑cycle control during development(PMID: 19550435). This can also occur through coding loss‑of‑function variants as well as through epigenetic silencing of CDKN1C, most commonly in the context of imprinting defects at the IC2/KvDMR1 region. This gene disease relationship is further supported by extensive experimental evidence. CDKN1C expression is reduced or absent in patient‑derived cells from individuals with Beckwith‑Wiedemann syndrome, including cases without identifiable coding variants, and chromatin immunoprecipitation studies demonstrate enrichment of repressive chromatin marks at the CDKN1C promoter in patient cells (PMIDs: 16061564, 14627666, and 26077438). In vitro functional studies show loss of protein function and abnormal cellular localization for Beckwith‑Wiedemann syndrome–associated variants(PMIDs: 26077438,10323243 and 11106355). Mouse models with targeted disruption of the maternally inherited CDKN1C allele exhibit prenatal overgrowth, organomegaly, skeletal abnormalities, and perinatal lethality, whereas disruption of the paternal allele alone does not result in abnormal phenotype, reflecting the parent‑of‑origin effects observed in humans (PMIDs: 9136926, 17517131, and 8646780). Additional experimental evidence exists in the literature, but the maximum score for experimental evidence has been reached. In summary, there is definitive evidence supporting the relationship between CDKN1C and autosomal dominant Beckwith‑Wiedemann syndrome with parent of origin effects. This relationship has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Hereditary Cancer Gene Curation Expert Panel on [04/24/2026] (SOP Version 12).
Inheritance Pattern: AD
Disease ID:MONDO:0005212
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0013873
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013873
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013873
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0008394
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007534
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0018573
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013873
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007534
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007534
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Endocrine; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Oncologic; Renal
Intervention: Endocrine; Oncologic
Rationale: While IMAGe syndrome may have a number of recognizable features, recognition may allow preventive/treatment measures related to adrenal insufficiency; In Beckwith-Wiedemann syndrome, surveillance and early detection of and treatment for malignancy may decrease morbidity and mortality; Recognition and surveillance for and treatment of neonatal hypoglycemia can be beneficial
Comments: The conditions may involve imprinting mechanisms
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CDKN1C variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001122630.2. 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 | 316 | 320 | |||
| missense | 6 | 6 | 521 | 17 | 550 | |
| nonsense | 26 | 4 | 1 | 31 | ||
| start loss | 1 | 2 | 3 | |||
| frameshift | 67 | 20 | 4 | 3 | 94 | |
| splice donor/acceptor (+/-2bp) | 1 | 3 | 5 | 9 | ||
| Total | 100 | 34 | 537 | 336 | 0 | 1007 |
Highest pathogenic variant AF is 0.0000022845759
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001116102.1 | 2 | MANE Select | |
| Ensembl | ENSP00000411257.2 | 2 | MANE Select | |
| RefSeq | NP_000067.1 | 2 | Standard | |
| RefSeq | NP_001116103.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cdkn1ca | Danio rerio | Structure: fast muscle cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell cycle - Homo sapiens (human)
- miR-targeted genes in epithelium - TarBase
- miR-targeted genes in lymphocytes - TarBase
- Primary Focal Segmental Glomerulosclerosis FSGS
- Dopaminergic Neurogenesis
Biological Process
- negative regulation of transcription by RNA polymerase II
- skeletal system development
- kidney development
- cell cycle arrest
- regulation of exit from mitosis
Molecular Function
- protein kinase inhibitor activity
- cyclin-dependent protein serine/threonine kinase inhibitor activity
- protein binding
- protein-containing complex binding
Cellular Component
- nucleus
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000414822
- Coding exons
- 2
- Length
- 2669
- 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 | 1.93 | 64 | 125 | 0.513 | 0.00000575 | 1912 |
| Missense (PolyPhen) | 14 | 36.694 | 0.38154 | 342 | ||
| Synonymous | -0.339 | 60 | 56.7 | 1.06 | 0.00000278 | 738 |
| Loss of Function | 2.20 | 0 | 5.65 | 0.00 | 2.43e-7 | 70 |
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: Potent tight-binding inhibitor of several G1 cyclin/CDK complexes (cyclin E-CDK2, cyclin D2-CDK4, and cyclin A-CDK2) and, to lesser extent, of the mitotic cyclin B-CDC2. Negative regulator of cell proliferation. May play a role in maintenance of the non- proliferative state throughout life.;
- Disease
- DISEASE: Beckwith-Wiedemann syndrome (BWS) [MIM:130650]: A disorder characterized by anterior abdominal wall defects including exomphalos (omphalocele), pre- and postnatal overgrowth, and macroglossia. Additional less frequent complications include specific developmental defects and a predisposition to embryonal tumors. {ECO:0000269|PubMed:10424811, ECO:0000269|PubMed:26077438}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (IMAGE) [MIM:614732]: A rare condition characterized by intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies. Patients with this condition may present shortly after birth with severe adrenal insufficiency, which can be life-threatening if not recognized early and commenced on steroid replacement therapy. Other reported features in this condition include, hypercalciuria and/or hypercalcemia, craniosynostosis, cleft palate, and scoliosis. {ECO:0000269|PubMed:22634751}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.781
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |