CDK4

protein-coding

cyclin dependent kinase 4, the group of Cyclin dependent kinases|MicroRNA protein coding host genes

Gene summary

The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000075.4

Inheritance

ClinVar variants

P:6U:632B:379

Top phenotype

Melanoma, cutaneous malignant, susceptibility to, 3

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr12:57,747,727-57,756,013

External References & Databases

Ensembl (ENSG00000135446)

Transcript & Mutation Effects

hg38 • Region Span ~8.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

melanoma, cutaneous malignant, susceptibility to, 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012183

Submitter: Ambry Genetics

melanoma, cutaneous malignant, susceptibility to, 3DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012183

Submitter: G2P

malignant pancreatic neoplasmMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0009831

Submitter: Genomics England PanelApp

melanoma, cutaneous malignant, susceptibility to, 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012183

Submitter: Labcorp Genetics (formerly Invitae)

melanoma, cutaneous malignant, susceptibility to, 3DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012183

Submitter: ClinGen

CDK4 was the second high risk melanoma susceptibility gene identified . CDK4 is an oncogene located within the 12q14 chromosomal region and encodes a protein that controls cell cycle progression through the G1 phase. To date mutations in this gene have been described in 17 melanoma-prone families and in all of them the mutation affects the same amino acid (Arginine 24): p.Arg24Cys and p.Arg24His (Potrony M, et al. 2015. PMID: 26488006). These R24C and R24H mutations lead to CDK4 behaving as a dominant oncoprotein through loss of binding to p16, its negative regulator. Thus, when CDK4 is mutated, p16INK4A cannot inhibit the CDK4 kinase activity resulting in the progression of the cell cycle. In an analysis of 17 families, median age at first melanoma diagnosis was 39 years, and the lifetime mutation penetrance based on the available data was estimated at 74%(Read J, et al. 2016.PMID: 26337759). Phenotypically, individuals with CDK4 mutations cannot be distinguished from those with CDKN2A mutations . Both mutations are characterized by numerous atypical nevi and multiple primary melanomas.(Lee KC, et al. 2015. PMID:30190834).

Clinical Genomic Database (CGD)

Melanoma, cutaneous malignant, susceptibility to, 3AD

Manifestation: Dermatologic; Oncologic

Intervention: Dermatologic; Oncologic

Rationale: Surveillance for melanoma in at-risk individuals (eg, with regular self-examination and clinical examination) may allow early detection and treatment, which may decrease morbidity and mortality

Refs: 7652577; 8528263; 9425228; 15880589; 21801156; 23384855; 23546221

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDK4 variants in ClinVar

13 Conditions Cataloged

Familial melanomaTotal: 918

Hereditary cancer-predisposing syndromeTotal: 708

Melanoma, cutaneous malignant, susceptibility to, 3Total: 354

not providedTotal: 164

not specifiedTotal: 124

CDK4-related disorderTotal: 34

Microcephaly 31, primary, autosomal recessiveTotal: 4

Hereditary cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000075.4. 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			6 clinvar	297 clinvar	36 clinvar	339
missense	2 clinvar		553 clinvar	46 clinvar		601
nonsense	1 clinvar	1 clinvar	20 clinvar			22
start loss						0
frameshift	1 clinvar	1 clinvar	41 clinvar			43
splice donor/acceptor (+/-2bp)			12 clinvar			12
Total	4	2	632	343	36	1017

Highest pathogenic variant AF is 0.0000027363449

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000075.4	RefSeq	NP_000066.1	7	MANE Select
ENST00000257904.11	Ensembl	ENSP00000257904.5	7	MANE Select
ENST00000312990.10	Ensembl	ENSP00000316889.6	5	Standard
ENST00000546489.5	Ensembl	ENSP00000447779.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Non-small cell lung cancer - Homo sapiens (human)
Chronic myeloid leukemia - Homo sapiens (human)
T cell receptor signaling pathway - Homo sapiens (human)
Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)

Biological Process

regulation of cyclin-dependent protein serine/threonine kinase activity
G1/S transition of mitotic cell cycle
lens development in camera-type eye
transcription initiation from RNA polymerase II promoter
protein phosphorylation

Molecular Function

cyclin-dependent protein serine/threonine kinase activity
protein binding
ATP binding
cyclin-dependent protein serine/threonine kinase regulator activity
cyclin binding

Cellular Component

cyclin-dependent protein kinase holoenzyme complex
chromatin
nucleus
nucleoplasm
transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000257904
Coding exons: 7
Length: 8287
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.49	115	170	0.678	0.0000100	1934
Missense (PolyPhen)		22	51.569	0.42661		674
Synonymous	-1.63	82	65.2	1.26	0.00000380	654
Loss of Function	2.61	5	16.4	0.305	0.00000112	158

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes 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 phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex. {ECO:0000269|PubMed:15241418, ECO:0000269|PubMed:18827403, ECO:0000269|PubMed:9003781}.;
Disease: DISEASE: Melanoma, cutaneous malignant 3 (CMM3) [MIM:609048]: A malignant neoplasm of melanocytes, arising de novo or from a pre- existing benign nevus, which occurs most often in the skin but also may involve other sites. {ECO:0000269|PubMed:7652577, ECO:0000269|PubMed:8528263, ECO:0000269|PubMed:9311594, ECO:0000269|PubMed:9425228}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.774

Intolerance Scores

LoFtool: 0.303
RVIS EVS: -0.3
RVIS percentile EVS: 32.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.998

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium