CDKN2A
cyclin dependent kinase inhibitor 2A
Basic information
Region (hg38): 9:21967751-21995301
Previous symbols: [ "CDKN2", "MLM" ]
Links
Phenotypes
GenCC
Source:
- familial atypical multiple mole melanoma syndrome (Supportive), mode of inheritance: AD
- melanoma and neural system tumor syndrome (Limited), mode of inheritance: AD
- melanoma-pancreatic cancer syndrome (Definitive), mode of inheritance: AD
- melanoma-pancreatic cancer syndrome (Strong), mode of inheritance: AD
- melanoma-pancreatic cancer syndrome (Strong), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Melanoma and neural system tumor syndrome; Melanoma, familial; Melanoma-pancreatic cancer syndrome | AD | Dermatologic; Oncologic | Surveillance and diagnosis of malignancies (potentially including, depending on the type of specific condition, melanoma and pancreatic cancer) may allow early diagnosis and treatment, potentially improving outcomes | Dermatologic; Oncologic | 7987387; 8153634; 7987388; 7666917; 7666916; 8653684; 9328469; 9699728; 9516223; 9603434; 9425228; 9916806; 10874641; 10956390; 1579459; 11506491; 11726555; 12019208; 11815963; 11807902; 12556369; 12700603; 15577313; 16822996; 17492760; 18178632; 20132244; 20653773; 21895773; 21325014; 21150883; 21801156; 20574843; 21570156; 21570154; 21625824; 22368299; 21614589; 22636603 |
| Other tumor types have been reported |
ClinVar
This is a list of variants' phenotypes submitted to
- Familial melanoma (846 variants)
- Hereditary cancer-predisposing syndrome (785 variants)
- not provided (264 variants)
- not specified (124 variants)
- Melanoma-pancreatic cancer syndrome (107 variants)
- Melanoma and neural system tumor syndrome (71 variants)
- Melanoma, cutaneous malignant, susceptibility to, 2 (29 variants)
- Squamous cell lung carcinoma (9 variants)
- Neoplasm (7 variants)
- Squamous cell carcinoma of the head and neck (7 variants)
- Malignant melanoma of skin (7 variants)
- Squamous cell carcinoma of the skin (6 variants)
- Pancreatic adenocarcinoma (6 variants)
- Gastric adenocarcinoma (6 variants)
- Melanoma-pancreatic cancer syndrome;Melanoma, cutaneous malignant, susceptibility to, 2;Melanoma and neural system tumor syndrome (5 variants)
- Transitional cell carcinoma of the bladder (4 variants)
- Hepatocellular carcinoma (4 variants)
- Lung adenocarcinoma (4 variants)
- Acute lymphoid leukemia (4 variants)
- Melanoma, cutaneous malignant, susceptibility to, 2;Melanoma and neural system tumor syndrome;Melanoma-pancreatic cancer syndrome (4 variants)
- Melanoma (4 variants)
- Melanoma and neural system tumor syndrome;Melanoma, cutaneous malignant, susceptibility to, 2;Melanoma-pancreatic cancer syndrome (4 variants)
- Neoplasm of the large intestine (3 variants)
- Lip and oral cavity carcinoma (2 variants)
- Ovarian cancer (2 variants)
- Malignant tumor of urinary bladder (2 variants)
- Maffucci syndrome (2 variants)
- Melanoma-pancreatic cancer syndrome;Melanoma and neural system tumor syndrome;Melanoma, cutaneous malignant, susceptibility to, 2 (2 variants)
- Melanoma and neural system tumor syndrome;Melanoma-pancreatic cancer syndrome (2 variants)
- CDKN2A-related condition (2 variants)
- Melanoma and neural system tumor syndrome;Melanoma-pancreatic cancer syndrome;Melanoma, cutaneous malignant, susceptibility to, 2 (2 variants)
- Neoplasm of ovary;Melanoma (1 variants)
- Inborn genetic diseases (1 variants)
- Gastric cancer (1 variants)
- Atypical endometrial hyperplasia (1 variants)
- Carcinoma of esophagus (1 variants)
- Melanoma-pancreatic cancer syndrome;Melanoma and neural system tumor syndrome (1 variants)
- Prostate adenocarcinoma (1 variants)
- Osteoblastic osteosarcoma (1 variants)
- Retinoblastoma (1 variants)
- Papillary renal cell carcinoma, sporadic (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the CDKN2A 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 | 149 | 152 | ||||
| missense | 31 | 535 | 32 | 606 | ||
| nonsense | 20 | 28 | ||||
| start loss | 10 | 10 | ||||
| frameshift | 36 | 11 | 56 | |||
| inframe indel | 12 | 14 | ||||
| splice donor/acceptor (+/-2bp) | 11 | |||||
| splice region ? | 1 | 2 | 19 | 5 | 27 | |
| non coding ? | 38 | 103 | 13 | 160 | ||
| Total | 68 | 57 | 611 | 286 | 15 |
Highest pathogenic variant AF is 0.0000131
Variants in CDKN2A
This is a list of pathogenic ClinVar variants found in the CDKN2A region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 9-21967856-G-C | Benign (Mar 03, 2015) | |||
| 9-21968006-C-A | Benign (Mar 03, 2015) | |||
| 9-21968160-G-A | not specified | Benign (Mar 03, 2015) | ||
| 9-21968200-C-G | Squamous cell lung carcinoma • not specified | Benign (Mar 03, 2015) | ||
| 9-21968216-C-G | Hereditary cancer-predisposing syndrome | Conflicting classifications of pathogenicity (Mar 02, 2017) | ||
| 9-21968216-C-T | Hereditary cancer-predisposing syndrome | Uncertain significance (Aug 26, 2019) | ||
| 9-21968218-CTCTGGTTCTTTCAATCGG-C | Hereditary cancer-predisposing syndrome | Uncertain significance (Apr 21, 2021) | ||
| 9-21968220-C-A | Familial melanoma • Hereditary cancer-predisposing syndrome • CDKN2A-related disorder | Conflicting classifications of pathogenicity (Apr 27, 2023) | ||
| 9-21968220-C-T | Hereditary cancer-predisposing syndrome | Likely benign (Aug 12, 2016) | ||
| 9-21968221-T-A | Hereditary cancer-predisposing syndrome | Conflicting classifications of pathogenicity (Jul 10, 2019) | ||
| 9-21968221-T-C | not specified • Hereditary cancer-predisposing syndrome • CDKN2A-related disorder | Likely benign (May 11, 2023) | ||
| 9-21968223-G-C | Hereditary cancer-predisposing syndrome • not specified | Benign/Likely benign (Aug 23, 2023) | ||
| 9-21968226-C-T | Hereditary cancer-predisposing syndrome | Uncertain significance (May 22, 2019) | ||
| 9-21968226-C-CT | Hereditary cancer-predisposing syndrome | Uncertain significance (Jan 05, 2024) | ||
| 9-21968229-T-G | Hereditary cancer-predisposing syndrome | Uncertain significance (Dec 27, 2019) | ||
| 9-21968230-C-A | Familial melanoma | Uncertain significance (Aug 03, 2023) | ||
| 9-21968230-C-T | Familial melanoma | Likely benign (Jun 27, 2019) | ||
| 9-21968232-A-G | Familial melanoma • Hereditary cancer-predisposing syndrome | Likely benign (Jan 18, 2024) | ||
| 9-21968233-T-A | Hereditary cancer-predisposing syndrome | Uncertain significance (Mar 30, 2022) | ||
| 9-21968234-C-A | Hereditary cancer-predisposing syndrome • Familial melanoma | Uncertain significance (Nov 20, 2023) | ||
| 9-21968234-C-T | Familial melanoma • Hereditary cancer-predisposing syndrome | Uncertain significance (Sep 06, 2023) | ||
| 9-21968234-CG-C | Hereditary cancer-predisposing syndrome | Uncertain significance (Jun 29, 2020) | ||
| 9-21968235-G-A | Familial melanoma • Hereditary cancer-predisposing syndrome | Likely benign (Jan 31, 2024) | ||
| 9-21968235-G-C | Hereditary cancer-predisposing syndrome • Familial melanoma | Likely benign (Nov 24, 2023) | ||
| 9-21968235-G-T | Familial melanoma | Likely benign (Jun 30, 2019) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| CDKN2A | protein_coding | protein_coding | ENST00000498124 | 3 | 27550 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.395 | 0.568 | 124976 | 0 | 5 | 124981 | 0.0000200 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | -1.01 | 136 | 107 | 1.28 | 0.00000486 | 1020 |
| Missense in Polyphen | 41 | 36.235 | 1.1315 | 349 | ||
| Synonymous | -0.512 | 56 | 51.3 | 1.09 | 0.00000245 | 384 |
| Loss of Function | 1.65 | 1 | 4.99 | 0.201 | 2.13e-7 | 53 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.0000686 | 0.0000617 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.0000367 | 0.0000356 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.00 | 0.00 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Capable of inducing cell cycle arrest in G1 and G2 phases. Acts as a tumor suppressor. Binds to MDM2 and blocks its nucleocytoplasmic shuttling by sequestering it in the nucleolus. This inhibits the oncogenic action of MDM2 by blocking MDM2- induced degradation of p53 and enhancing p53-dependent transactivation and apoptosis. Also induces G2 arrest and apoptosis in a p53-independent manner by preventing the activation of cyclin B1/CDC2 complexes. Binds to BCL6 and down-regulates BCL6-induced transcriptional repression. Binds to E2F1 and MYC and blocks their transcriptional activator activity but has no effect on MYC transcriptional repression. Binds to TOP1/TOPOI and stimulates its activity. This complex binds to rRNA gene promoters and may play a role in rRNA transcription and/or maturation. Interacts with NPM1/B23 and promotes its polyubiquitination and degradation, thus inhibiting rRNA processing. Interacts with COMMD1 and promotes its 'Lys63'-linked polyubiquitination. Interacts with UBE2I/UBC9 and enhances sumoylation of a number of its binding partners including MDM2 and E2F1. Binds to HUWE1 and represses its ubiquitin ligase activity. May play a role in controlling cell proliferation and apoptosis during mammary gland development. Isoform smARF may be involved in regulation of autophagy and caspase-independent cell death; the short-lived mitochondrial isoform is stabilized by C1QBP. {ECO:0000269|PubMed:11314011, ECO:0000269|PubMed:11314038, ECO:0000269|PubMed:12660818, ECO:0000269|PubMed:14636574, ECO:0000269|PubMed:15361825, ECO:0000269|PubMed:15567177, ECO:0000269|PubMed:15876874, ECO:0000269|PubMed:15989956, ECO:0000269|PubMed:16713577, ECO:0000269|PubMed:18305112, ECO:0000269|PubMed:22094112, ECO:0000269|PubMed:9724636}.;
- Pathway
- Non-small cell lung cancer - Homo sapiens (human);Chronic myeloid leukemia - Homo sapiens (human);Melanoma - 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);HTLV-I infection - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Glioma - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Pancreatic cancer - Homo sapiens (human);Cell Cycle;TP53 Network;Apoptosis Modulation and Signaling;miR-targeted genes in epithelium - TarBase;miR-targeted genes in lymphocytes - TarBase;Signaling Pathways in Glioblastoma;Apoptosis;Bladder Cancer;Vitamin D Receptor Pathway;Oncogene Induced Senescence;Oxidative Stress Induced Senescence;Photodynamic therapy-induced AP-1 survival signaling.;Apoptotic Signaling Pathway;Transcriptional regulation by RUNX3;Tumor suppressor activity of SMARCB1;G1 to S cell cycle control;Senescence and Autophagy in Cancer;DNA Damage Response (only ATM dependent);Regulation of RUNX3 expression and activity;Gene expression (Transcription);RUNX3 regulates p14-ARF;Transcriptional regulation by RUNX3;tumor suppressor arf inhibits ribosomal biogenesis;cell cycle: g1/s check point;cyclins and cell cycle regulation;ctcf: first multivalent nuclear factor;Generic Transcription Pathway;Oncogene Induced Senescence;Oxidative Stress Induced Senescence;SUMOylation of DNA damage response and repair proteins;Senescence-Associated Secretory Phenotype (SASP);Cellular Senescence;SUMOylation of transcription factors;Cellular responses to stress;Post-translational protein modification;SUMO E3 ligases SUMOylate target proteins;Metabolism of proteins;RNA Polymerase II Transcription;Stabilization of p53;p53-Dependent G1 DNA Damage Response;p53-Dependent G1/S DNA damage checkpoint;G1/S DNA Damage Checkpoints;Cell Cycle Checkpoints;Hedgehog;Cyclin D associated events in G1;G1 Phase;Hypoxic and oxygen homeostasis regulation of HIF-1-alpha;Mitotic G1-G1/S phases;SUMOylation;Cellular responses to external stimuli;Validated transcriptional targets of TAp63 isoforms;Coregulation of Androgen receptor activity;Regulation of TP53 Degradation;Regulation of TP53 Expression and Degradation;C-MYB transcription factor network;C-MYC pathway;Regulation of TP53 Activity;Transcriptional Regulation by TP53;Cell Cycle;Cell Cycle, Mitotic;Regulation of nuclear beta catenin signaling and target gene transcription;Validated transcriptional targets of deltaNp63 isoforms;AP-1 transcription factor network;FOXM1 transcription factor network;Validated transcriptional targets of AP1 family members Fra1 and Fra2;Regulation of retinoblastoma protein;E2F transcription factor network;p53 pathway
(Consensus)
Recessive Scores
- pRec
- 0.0685
Intolerance Scores
- loftool
- 0.144
- rvis_EVS
- 0.73
- rvis_percentile_EVS
- 85.98
Haploinsufficiency Scores
- pHI
- 0.0304
- hipred
- Y
- hipred_score
- 0.554
- ghis
- 0.440
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.824
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Cdkn2a
- 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; muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; immune system phenotype; skeleton phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system 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; 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; vision/eye phenotype;
Gene ontology
- Biological process
- G1/S transition of mitotic cell cycle;negative regulation of cell-matrix adhesion;cell cycle arrest;Ras protein signal transduction;negative regulation of cell population proliferation;negative regulation of cell growth;negative regulation of NF-kappaB transcription factor activity;positive regulation of smooth muscle cell apoptotic process;senescence-associated heterochromatin focus assembly;negative regulation of phosphorylation;negative regulation of cyclin-dependent protein serine/threonine kinase activity;negative regulation of transcription, DNA-templated;cellular senescence;replicative senescence;positive regulation of macrophage apoptotic process;positive regulation of cellular senescence
- Cellular component
- nucleus;cytoplasm;cytosol;senescence-associated heterochromatin focus
- Molecular function
- RNA binding;cyclin-dependent protein serine/threonine kinase inhibitor activity;protein binding;protein kinase binding;NF-kappaB binding