CDKN2A

protein-coding

cyclin dependent kinase inhibitor 2A

Gene summary

This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]

Previous symbols:

CDKN2
MLM

MANE transcript

NM_000077.5

Inheritance

ClinVar variants

P:188U:508B:252

Top phenotype

Melanoma-astrocytoma syndrome; Melanoma, familial; Melanoma-pancreatic cancer syndrome

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr9:21,967,752-21,995,301

External References & Databases

Ensembl (ENSG00000147889)

UniProt (P42771, Q8N726)

Transcript & Mutation Effects

hg38 • Region Span ~27.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

melanoma, cutaneous malignant, susceptibility to, 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007964

Submitter: G2P

melanoma-pancreatic cancer syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011713

Submitter: Labcorp Genetics (formerly Invitae)

melanoma-pancreatic cancer syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011713

Submitter: ClinGen

There is abundant evidence published associating the CDKN2A gene with melanoma-pancreatic cancer syndrome since the gene-disease relationship was first proposed by Hussussian et al. (1994). Multiple case level studies have been performed with melanoma patients that have variants in the CDKN2A gene. Over 200 families has been reported worldwide and many variants are founder variants. The CDKN2A gene produces two different proteins p14(ARF) and p16(INK4a) by alternative splicing. Both proteins function as inhibitors of cell cycle progression, but regulate cell cycle through the TP53 pathway and the RB1 pathway respectively. CDKN2A germline mutations that result in the disruption of one of each transcripts or both have all been reported in patients with melanoma. But the spectrum of disease is slightly different in patients' phenotypes and in the mouse models. The patients with disruption of p14 also can have nerve sheath tumors, which has been reported in a few studies. CDK4 that is inhibited by p16 is also associate with Melanoma, cutaneous malignant. Assessment of CDK4 binding and p16 subcellular localization can accurately and rapidly determine the functional significance of melanoma associated p16INK4a mutations. Multiple in vivo knock-out mouse models with CDKN2A deficiency have been established to show tumorigenesis of melanoma and other types of tumors. All of these types of evidence are consistent with a definitive relationship between the CDKN2A gene and melanoma-pancreatic cancer syndrome.

melanoma and neural system tumor syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007967

Submitter: Ambry Genetics

melanoma-pancreatic cancer syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011713

Submitter: Genomics England PanelApp

familial atypical multiple mole melanoma syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018453

Submitter: Orphanet

melanoma-pancreatic cancer syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011713

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Melanoma-astrocytoma syndrome; Melanoma, familial; Melanoma-pancreatic cancer syndromeAD

Manifestation: Dermatologic; Oncologic

Intervention: Dermatologic; Oncologic

Rationale: 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

Comments: Other tumor types have been reported

Refs: 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

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDKN2A variants in ClinVar

24 Conditions Cataloged

Familial melanomaTotal: 768

Hereditary cancer-predisposing syndromeTotal: 764

Melanoma-pancreatic cancer syndromeTotal: 307

not providedTotal: 236

Melanoma and neural system tumor syndromeTotal: 109

not specifiedTotal: 107

Melanoma, cutaneous malignant, susceptibility to, 2Total: 50

CDKN2A-related disorderTotal: 28

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000077.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	2 clinvar		16 clinvar	200 clinvar	11 clinvar	229
missense	8 clinvar	66 clinvar	454 clinvar	39 clinvar	2 clinvar	569
nonsense	21 clinvar	1 clinvar	2 clinvar			24
start loss			8 clinvar			8
frameshift	55 clinvar	18 clinvar	20 clinvar			93
splice donor/acceptor (+/-2bp)	6 clinvar	11 clinvar	8 clinvar			25
Total	92	96	508	239	13	948

Highest pathogenic variant AF is 0.00011028801

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000077.5	RefSeq	NP_000068.1	3	MANE Select
ENST00000304494.10	Ensembl	ENSP00000307101.5	3	MANE Select
NM_001195132.2	RefSeq	NP_001182061.1	3	Standard
NM_001363763.2	RefSeq	NP_001350692.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

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

Molecular Function

RNA binding
cyclin-dependent protein serine/threonine kinase inhibitor activity
protein binding
protein kinase binding
NF-kappaB binding

Cellular Component

nucleus
cytoplasm
cytosol
senescence-associated heterochromatin focus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000498124
Coding exons: 3
Length: 27550
Individuals with no LoFs: 124976
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 124981
p: 0.0000200

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.01	136	107	1.28	0.00000486	1020
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000069	0.000062	rare
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)	0.000037	0.000036	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

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}.;

Recessive Scores

pRec: 0.0685

Intolerance Scores

LoFtool: 0.144
RVIS EVS: 0.73
RVIS percentile EVS: 85.98

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.824

Gene Damage Prediction

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