GeneBe

CDKN1B

protein-coding

cyclin dependent kinase inhibitor 1B

Gene summary

This gene encodes a cyclin-dependent kinase inhibitor, which shares a limited similarity with CDK inhibitor CDKN1A/p21. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. The degradation of this protein, which is triggered by its CDK dependent phosphorylation and subsequent ubiquitination by SCF complexes, is required for the cellular transition from quiescence to the proliferative state. Mutations in this gene are associated with multiple endocrine neoplasia type IV (MEN4). [provided by RefSeq, Apr 2014]

MANE transcript

NM_004064.5

Inheritance

AD

ClinVar variants

P:137U:563B:311

Top phenotype

Multiple endocrine neoplasia, type IV

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr12:12,685,498-12,722,369

External References & Databases

Ensembl (ENSG00000111276)NCBI Gene (1027)OMIM (600778)HGNC:1785GenCCUniProt (P46527)AlphaFoldClinVar (CDKN1B)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~36.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

multiple endocrine neoplasia type 4MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012552

Submitter: Ambry Genetics

multiple endocrine neoplasia type 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012552

Submitter: Labcorp Genetics (formerly Invitae)

multiple endocrine neoplasia type 4DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012552

Submitter: ClinGen

There is abundant evidence published associating the CDKN1B gene with multiple endocrine neoplasia type 4 (MEN4) since the gene-disease relationship was first proposed by Pellegata et al. (2006). Germline CDKN1B mutations are rare, but nine case level studies have been performed so far with MEN4 patients that have variants in the CDKN1B gene. CDKN1B is a negative regulator of cell cycle progression, and its loss is associated with disease progression and unfavorable outcome in many cancer types. CDKN1B show very low nuclear expression in parathyroid adenoma cells and endocrine pancreatic tumor from MEN4 patients. p27wt inhibits the growth of p27-negative GH3 cells in clonogenic assay while p27W76X does not. Mouse and Rat models have been established to show the development of multiple endocrine tumors with CDKN1B deficiency. All of these types of evidence are consistent with a definitive relationship between the CDKN1B gene and multiple endocrine neoplasia type 4 (MEN4).

hereditary nonpolyposis colon cancerLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0018630

Submitter: ClinGen

multiple endocrine neoplasia type 4SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012552

Submitter: Orphanet

multiple endocrine neoplasiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0017169

Submitter: G2P

Clinical Genomic Database (CGD)

Multiple endocrine neoplasia, type IVAD

Manifestation: Endocrine; Oncologic

Intervention: Endocrine; Oncologic

Rationale: Surveillance and risk awareness may allow prompt detection and treatment of associated neoplasms (in affected individuals, these have been reported as including primary hyperparathyroidism likely due to underlying neoplasm, pituitary adenoma, and renal angiomyolipoma), which may decrease associated morbidity and mortality

Refs: 17030811; 20507346; 20824794; 21289244; 22129891; 23555276; 24819502Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDKN1B variants in ClinVar

12 Conditions Cataloged
Multiple endocrine neoplasia type 4Total: 806
Hereditary cancer-predisposing syndromeTotal: 788
not providedTotal: 139
CDKN1B-related disorderTotal: 33
not specifiedTotal: 19
Ovarian cancerTotal: 4
Primary hyperparathyroidismTotal: 3
Hereditary nonpolyposis colon cancerTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004064.5. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
3
clinvar
225
clinvar
2
clinvar
 231
missense
2
clinvar
1
clinvar
518
clinvar
80
clinvar
2
clinvar
 603
nonsense
28
clinvar
8
clinvar
1
clinvar
 37
start loss
1
clinvar
6
clinvar
2
clinvar
 9
frameshift
76
clinvar
18
clinvar
29
clinvar
 123
splice donor/acceptor (+/-2bp)
2
clinvar
6
clinvar
 8
Total1073056330741011

Highest pathogenic variant AF is 0.0000020534892

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_004064.5RefSeqNP_004055.12MANE Select
ENST00000228872.9EnsemblENSP00000228872.42MANE Select
ENST00000396340.1EnsemblENSP00000379629.12Standard
ENST00000396340.2EnsemblENSP00000379629.12Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • PI3K-Akt signaling pathway - Homo sapiens (human)
  • Chronic myeloid leukemia - Homo sapiens (human)
  • Gastric cancer - Homo sapiens (human)
  • AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
  • Cushing,s syndrome - Homo sapiens (human)

Biological Process

  • regulation of cyclin-dependent protein serine/threonine kinase activity
  • G1/S transition of mitotic cell cycle
  • response to hypoxia
  • placenta development
  • potassium ion transport

Molecular Function

  • cyclin-dependent protein serine/threonine kinase activity
  • protein kinase inhibitor activity
  • cyclin-dependent protein serine/threonine kinase inhibitor activity
  • transforming growth factor beta receptor, cytoplasmic mediator activity
  • protein binding

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm
  • endosome
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000228872
Coding exons
2
Length
7314
Individuals with no LoFs
125727
Homozygous LoFs
0
Heterozygous LoFs
6
Defined
125733
p
0.0000239
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-1.851641101.500.000005161295
Missense (PolyPhen)3126.1341.1862326
Synonymous-5.178844.21.990.00000222384
Loss of Function2.1717.360.1363.19e-791

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish0.000100.000099rare
East Asian00.0absent
Finnish0.0000470.000046rare
European (Non-Finnish)0.0000270.000026rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Important regulator of cell cycle progression. Inhibits the kinase activity of CDK2 bound to cyclin A, but has little inhibitory activity on CDK2 bound to SPDYA (PubMed:28666995). Involved in G1 arrest. Potent inhibitor of cyclin E- and cyclin A- CDK2 complexes. Forms a complex with cyclin type D-CDK4 complexes and is involved in the assembly, stability, and modulation of CCND1-CDK4 complex activation. Acts either as an inhibitor or an activator of cyclin type D-CDK4 complexes depending on its phosphorylation state and/or stoichometry. {ECO:0000269|PubMed:10831586, ECO:0000269|PubMed:12244301, ECO:0000269|PubMed:16782892, ECO:0000269|PubMed:17254966, ECO:0000269|PubMed:19075005, ECO:0000269|PubMed:28666995}.;
Disease
DISEASE: Multiple endocrine neoplasia 4 (MEN4) [MIM:610755]: Multiple endocrine neoplasia (MEN) syndromes are inherited cancer syndromes of the thyroid. MEN4 is a MEN-like syndrome with a phenotypic overlap of both MEN1 and MEN2. {ECO:0000269|PubMed:17030811}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.689

Intolerance Scores

LoFtool
0.213
RVIS EVS
-0.01
RVIS percentile EVS
53.51

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.628

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium
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