TIMP2

protein-coding

TIMP metallopeptidase inhibitor 2, the group of Tissue inhibitor of metallopeptidases

Gene summary

This gene is a member of the TIMP gene family. The proteins encoded by this gene family are natural inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix. In addition to an inhibitory role against metalloproteinases, the encoded protein has a unique role among TIMP family members in its ability to directly suppress the proliferation of endothelial cells. As a result, the encoded protein may be critical to the maintenance of tissue homeostasis by suppressing the proliferation of quiescent tissues in response to angiogenic factors, and by inhibiting protease activity in tissues undergoing remodelling of the extracellular matrix. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003255.5

Inheritance

—

ClinVar variants

U:22B:2

Top phenotype

TIMP2-related disorder

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr17:78,852,977-78,925,387

External References & Databases

Ensembl (ENSG00000035862)

Transcript & Mutation Effects

hg38 • Region Span ~72.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TIMP2 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 20

TIMP2-related disorderTotal: 3

not providedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003255.5. 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			1 clinvar	2 clinvar		3
missense			21 clinvar			21
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	22	2	0	24

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003255.5	RefSeq	NP_003246.1	5	MANE Select
ENST00000262768.11	Ensembl	ENSP00000262768.6	5	MANE Select
ENST00000536189.6	Ensembl	ENSP00000441724.1	3	Standard
ENST00000585421.5	Ensembl	ENSP00000467584.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
timp2a	Danio rerio	Structure: whole organism Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

timp2a

Danio rerio

Structure: whole organism

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Matrix Metalloproteinases
Angiogenesis
Angiogenesis overview
IL1 and megakaryocytes in obesity
Vitamin D Receptor Pathway

Biological Process

central nervous system development
aging
negative regulation of cell population proliferation
response to hormone
response to organic substance

Molecular Function

protease binding
integrin binding
protein binding
metalloendopeptidase inhibitor activity
zinc ion binding

Cellular Component

extracellular region
extracellular space
cell surface
growth cone
extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262768
Coding exons: 5
Length: 72411
Individuals with no LoFs: 125545
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125547
p: 0.00000797

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.61	71	121	0.589	0.00000747	1444
Missense (PolyPhen)		20	51.63	0.38737		594
Synonymous	-0.0323	54	53.7	1.01	0.00000436	408
Loss of Function	2.56	1	9.50	0.105	4.04e-7	123

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	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor. Known to act on MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-13, MMP-14, MMP-15, MMP-16 and MMP-19. {ECO:0000269|PubMed:11710594, ECO:0000269|PubMed:2554304, ECO:0000269|PubMed:2793861}.;

Intolerance Scores

LoFtool: 0.197
RVIS EVS: -0.32
RVIS percentile EVS: 31.46

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.760

Gene Damage Prediction

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