CDKN2B

protein-coding

cyclin dependent kinase inhibitor 2B

Gene summary

This gene lies adjacent to the tumor suppressor gene CDKN2A in a region that is frequently mutated and deleted in a wide variety of tumors. This gene encodes a cyclin-dependent kinase inhibitor, which forms a complex with CDK4 or CDK6, and prevents the activation of the CDK kinases, thus the encoded protein functions as a cell growth regulator that controls cell cycle G1 progression. The expression of this gene was found to be dramatically induced by TGF beta, which suggested its role in the TGF beta induced growth inhibition. Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004936.4

Inheritance

ClinVar variants

U:27B:9

Top phenotype

CDKN2B-related condition

gnomAD constraint

pLI —, LoF o/e 0.93

Max pathogenic AF

—

Genomic locus

chr9:22,002,903-22,009,305

External References & Databases

Ensembl (ENSG00000147883)

Transcript & Mutation Effects

hg38 • Region Span ~6.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

renal cell carcinomaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005086

Submitter: Genomics England PanelApp

glaucoma 1, open angle, ELIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007665

Submitter: Ambry Genetics

multiple endocrine neoplasiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0017169

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDKN2B variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 35

not providedTotal: 7

CDKN2B-related conditionTotal: 2

Multiple endocrine neoplasiaTotal: 1

Acute lymphoid leukemiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004936.4. 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				5 clinvar	1 clinvar	6
missense			26 clinvar	3 clinvar		29
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	0	0	27	8	1	36

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004936.4	RefSeq	NP_004927.2	2	MANE Select
ENST00000276925.7	Ensembl	ENSP00000276925.6	2	MANE Select
NM_078487.2	RefSeq	NP_511042.1	1	Standard
ENST00000380142.5	Ensembl	ENSP00000369487.4	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gastric cancer - Homo sapiens (human)
TGF-beta signaling pathway - Homo sapiens (human)
Cushing,s syndrome - Homo sapiens (human)
Cell cycle - Homo sapiens (human)
Small cell lung cancer - Homo sapiens (human)

Biological Process

regulation of cyclin-dependent protein serine/threonine kinase activity
G2/M transition of mitotic cell cycle
cell cycle arrest
mitotic cell cycle checkpoint
negative regulation of cell population proliferation

Molecular Function

cyclin-dependent protein serine/threonine kinase inhibitor activity
protein binding
protein kinase binding

Cellular Component

nucleus
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000276925
Coding exons: 2
Length: 6461
Individuals with no LoFs: 125007
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125019
p: 0.0000480

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.695	112	93.1	1.20	0.00000490	863
Missense (PolyPhen)		40	33.338	1.1998		320
Synonymous	-0.476	47	43.0	1.09	0.00000236	321
Loss of Function	0.109	3	3.21	0.934	1.41e-7	29

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
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)	0.000088	0.000080	rare
South Asian	0.00010	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Interacts strongly with CDK4 and CDK6. Potent inhibitor. Potential effector of TGF-beta induced cell cycle arrest.;

Recessive Scores

pRec: 0.406

Intolerance Scores

LoFtool: 0.383
RVIS EVS: 0.1
RVIS percentile EVS: 61.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.801

Gene Damage Prediction

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