CDK4

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

Basic information

Region (hg38): 12:57747726-57756013

Links

ENSG00000135446 ∙ NCBI:1019 ∙ OMIM:123829 ∙ HGNC:1773 ∙ Uniprot:P11802 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• malignant pancreatic neoplasm (Moderate), mode of inheritance: AD
• melanoma, cutaneous malignant, susceptibility to, 3 (Strong), mode of inheritance: AD
• melanoma, cutaneous malignant, susceptibility to, 3 (Strong), mode of inheritance: AD
• melanoma, cutaneous malignant, susceptibility to, 3 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Melanoma, cutaneous malignant, susceptibility to, 3	AD	Dermatologic; Oncologic	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	Dermatologic; Oncologic	7652577; 8528263; 9425228; 15880589; 21801156; 23384855; 23546221

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CDK4 gene.

• Familial melanoma (700 variants)
• Hereditary cancer-predisposing syndrome (469 variants)
• not provided (133 variants)
• not specified (96 variants)
• Melanoma, cutaneous malignant, susceptibility to, 3 (65 variants)
• CDK4-related condition (7 variants)
• Cutaneous Malignant Melanoma, Dominant (5 variants)
• Multiple myeloma (2 variants)
• Lung adenocarcinoma (2 variants)
• Malignant melanoma of skin (2 variants)
• Ewing sarcoma (1 variants)
• Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (1 variants)
• Melanoma (1 variants)
• Ovarian cancer (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CDK4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	203	2	210
missense	2		416	17		435
nonsense			17			17
start loss						0
frameshift			29			29
inframe indel			10			10
splice donor/acceptor (+/-2bp)			5			5
splice region			27	31	1	59
non coding			28	88	17	133
Total	2	0	510	308	19

Variants in CDK4

This is a list of pathogenic ClinVar variants found in the CDK4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-57747747-C-CT		Cutaneous Malignant Melanoma, Dominant	Uncertain significance (Jun 14, 2016)
12-57747761-GAC-G		Cutaneous Malignant Melanoma, Dominant	Uncertain significance (Jun 14, 2016)
12-57747774-G-A		Melanoma, cutaneous malignant, susceptibility to, 3	Benign (Jan 13, 2018)
12-57747791-G-A		Melanoma, cutaneous malignant, susceptibility to, 3	Uncertain significance (Apr 27, 2017)
12-57747819-C-T		Melanoma, cutaneous malignant, susceptibility to, 3	Benign (Jan 12, 2018)
12-57747835-C-T		Melanoma, cutaneous malignant, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
12-57747836-G-A		Melanoma, cutaneous malignant, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
12-57748004-C-T		Melanoma, cutaneous malignant, susceptibility to, 3	Benign (Jan 13, 2018)
12-57748034-G-A		Melanoma, cutaneous malignant, susceptibility to, 3	Benign (Jan 12, 2018)
12-57748046-A-G		Melanoma, cutaneous malignant, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
12-57748088-G-C		Melanoma, cutaneous malignant, susceptibility to, 3	Benign (Jan 13, 2018)
12-57748101-C-T		Melanoma, cutaneous malignant, susceptibility to, 3	Uncertain significance (Jan 12, 2018)
12-57748155-A-C		Melanoma, cutaneous malignant, susceptibility to, 3	Benign (Jan 13, 2018)
12-57748192-A-G		Melanoma, cutaneous malignant, susceptibility to, 3	Uncertain significance (Jan 12, 2018)
12-57748206-C-T		Melanoma, cutaneous malignant, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
12-57748221-TA-T		Cutaneous Malignant Melanoma, Dominant	Uncertain significance (Jun 14, 2016)
12-57748221-T-TA		Cutaneous Malignant Melanoma, Dominant	Uncertain significance (Jun 14, 2016)
12-57748254-T-C		Melanoma, cutaneous malignant, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
12-57748279-C-A		Melanoma, cutaneous malignant, susceptibility to, 3	Uncertain significance (Mar 18, 2022)
12-57748315-C-T		Melanoma, cutaneous malignant, susceptibility to, 3	Benign (Jan 13, 2018)
12-57748513-C-G		not specified	Likely benign (Mar 09, 2016)
12-57748520-A-G		Familial melanoma	Uncertain significance (Jul 27, 2016)
12-57748523-G-A		not specified	Uncertain significance (Nov 22, 2021)
12-57748526-C-A		Hereditary cancer-predisposing syndrome • Familial melanoma • CDK4-related disorder	Uncertain significance (Aug 31, 2022)
12-57748527-A-T		Familial melanoma	Uncertain significance (Aug 16, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CDK4	protein_coding	protein_coding	ENST00000257904	7	8287

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0629	0.934	125737	0	11	125748	0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.49	115	170	0.678	0.0000100	1934
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000615	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000616	0.0000615
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.000163	0.000163

dbNSFP

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.
• Pathway: 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);Melanoma - Homo sapiens (human);AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Bladder cancer - Homo sapiens (human);Cell cycle - Homo sapiens (human);p53 signaling pathway - Homo sapiens (human);Tight junction - Homo sapiens (human);Small cell lung cancer - Homo sapiens (human);Breast cancer - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Glioma - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Measles - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Pancreatic cancer - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Cell Cycle;miRNA Regulation of DNA Damage Response;Human Thyroid Stimulating Hormone (TSH) signaling pathway;Signaling Pathways in Glioblastoma;Spinal Cord Injury;Retinoblastoma (RB) in Cancer;Bladder Cancer;PPAR Alpha Pathway;Nuclear Receptors Meta-Pathway;Ovarian Infertility Genes;T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection;H19 action Rb-E2F1 signaling and CDK-β-catenin activity;PI3K-Akt Signaling Pathway;Tumor suppressor activity of SMARCB1;G1 to S cell cycle control;DNA Damage Response;Signaling by PTK6;Transcriptional regulation by RUNX2;Signal Transduction;Gene expression (Transcription);influence of ras and rho proteins on g1 to s transition;estrogen responsive protein efp controls cell cycle and breast tumors growth;cell cycle: g1/s check point;cyclins and cell cycle regulation;Generic Transcription Pathway;Oncogene Induced Senescence;Oxidative Stress Induced Senescence;Senescence-Associated Secretory Phenotype (SASP);Cellular Senescence;Cellular responses to stress;RNA Polymerase II Transcription;RMTs methylate histone arginines;Chromatin modifying enzymes;Cyclin D associated events in G1;G1 Phase;SCF(Skp2)-mediated degradation of p27/p21;Cyclin E associated events during G1/S transition ;ATF-2 transcription factor network;PTK6 Regulates Cell Cycle;Mitotic G1-G1/S phases;Cyclin A:Cdk2-associated events at S phase entry;BCR;Ubiquitin-dependent degradation of Cyclin D1;Ubiquitin-dependent degradation of Cyclin D;S Phase;Cellular responses to external stimuli;IL-7 signaling;p53 signaling pathway;TGF_beta_Receptor;rb tumor suppressor/checkpoint signaling in response to dna damage;JAK STAT pathway and regulation;Signaling by Non-Receptor Tyrosine Kinases;G1/S Transition;EPO signaling;Chromatin organization;Cell Cycle;VEGF;Cell Cycle, Mitotic;Validated targets of C-MYC transcriptional activation;Calcineurin-regulated NFAT-dependent transcription in lymphocytes;FOXM1 transcription factor network;Regulation of retinoblastoma protein;Regulation of nuclear SMAD2/3 signaling (Consensus)

Recessive Scores

• pRec: 0.774

Intolerance Scores

• loftool: 0.303
• rvis_EVS: -0.3
• rvis_percentile_EVS: 32.62

Haploinsufficiency Scores

• pHI: 1.00
• hipred: Y
• hipred_score: 0.831
• ghis: 0.692

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.998

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cdk4
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland phenotype; cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype; vision/eye phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; neoplasm; pigmentation phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; immune system phenotype; renal/urinary system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype

Gene ontology

• 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;signal transduction;circadian rhythm;positive regulation of cell population proliferation;response to toxic substance;response to lead ion;regulation of gene expression;positive regulation of G2/M transition of mitotic cell cycle;animal organ regeneration;cellular response to insulin stimulus;response to testosterone;regulation of multicellular organism growth;response to drug;positive regulation of apoptotic process;positive regulation of translation;positive regulation of cell cycle;positive regulation of cell size;regulation of insulin receptor signaling pathway;regulation of lipid biosynthetic process;positive regulation of fibroblast proliferation;regulation of lipid catabolic process;cell division;response to hyperoxia;adipose tissue development;negative regulation of cell cycle arrest;cellular response to lipopolysaccharide;cellular response to interleukin-4;cellular response to phorbol 13-acetate 12-myristate;cellular response to ionomycin
• Cellular component: cyclin-dependent protein kinase holoenzyme complex;chromatin;nucleus;nucleoplasm;transcription factor complex;nucleolus;cytosol;bicellular tight junction;nuclear membrane;perinuclear region of cytoplasm;cyclin D2-CDK4 complex
• Molecular function: cyclin-dependent protein serine/threonine kinase activity;protein binding;ATP binding;cyclin-dependent protein serine/threonine kinase regulator activity;cyclin binding;protein-containing complex binding