ANGPT2

protein-coding

angiopoietin 2, the group of Fibrinogen C domain containing|Receptor ligands

Gene summary

This gene belongs to the angiopoietin family of growth factors. The protein encoded by this gene is an antagonist of angiopoietin 1, and both angiopoietin 1 and angiopoietin 2 are ligands for the endothelial TEK receptor tyrosine kinase. Angiopoietin 2 is upregulated in multiple inflammatory diseases and is implicated in the direct control of inflammation-related signaling pathways. The encoded protein affects angiogenesis during embryogenesis and tumorigenesis, disrupts the vascular remodeling ability of angiopoietin 1, and may induce endothelial cell apoptosis. This gene serves a prognostic biomarker for acute respiratory distress syndrome. [provided by RefSeq, Aug 2020]

MANE transcript

NM_001118887.2

Inheritance

SD, AD

ClinVar variants

P:2U:83B:24

Top phenotype

Lymphatic malformation 10

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr8:6,499,632-6,563,409

External References & Databases

Ensembl (ENSG00000091879)

Transcript & Mutation Effects

hg38 • Region Span ~63.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lymphatic malformation 10LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0023662

Submitter: Labcorp Genetics (formerly Invitae)

lymphatic malformation 10STRONG

Inheritance Pattern: SD

Disease ID:MONDO:0023662

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Lymphatic malformation 10AD

Manifestation: Allergy/Immunology/Infectious; Cardiovascular

Intervention: Allergy/Immunology/Infectious

Rationale: The condition involves lymphatic malformations, and in some individuals, progression to cellulitis has been reported, such that awareness may allow prompt treatment of infectious sequelae

Refs: 32908006

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ANGPT2 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 75

not providedTotal: 29

Lymphatic malformation 10Total: 5

ANGPT2-related disorderTotal: 2

Microcephaly 1, primary, autosomal recessiveTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001118887.2. 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	9 clinvar	4 clinvar	14
missense	2 clinvar		80 clinvar	7 clinvar	4 clinvar	93
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	2	0	83	16	8	109

Highest pathogenic variant AF is 0.00010284547

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001118887.2	RefSeq	NP_001112359.1	9	MANE Select
ENST00000629816.3	Ensembl	ENSP00000486858.2	9	MANE Select
NM_001118888.2	RefSeq	NP_001112360.1	8	Standard
NM_001147.3	RefSeq	NP_001138.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
angpt2b	Danio rerio	Structure: subintestinal vein Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

angpt2b

Danio rerio

Structure: subintestinal vein

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
HIF-1 signaling pathway - Homo sapiens (human)
Rap1 signaling pathway - Homo sapiens (human)
Ras signaling pathway - Homo sapiens (human)

Biological Process

angiogenesis
response to hypoxia
signal transduction
germ cell development
response to radiation

Molecular Function

signaling receptor binding
protein binding
receptor tyrosine kinase binding
metal ion binding

Cellular Component

extracellular region
extracellular space
nucleus
plasma membrane
cell projection

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000325203
Coding exons: 9
Length: 63759
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.527	298	273	1.09	0.0000145	3308
Missense (PolyPhen)		74	107.57	0.68794		1285
Synonymous	-2.15	130	102	1.27	0.00000629	848
Loss of Function	4.02	5	27.9	0.179	0.00000127	329

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	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000070	0.000070	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds to TEK/TIE2, competing for the ANGPT1 binding site, and modulating ANGPT1 signaling. Can induce tyrosine phosphorylation of TEK/TIE2 in the absence of ANGPT1. In the absence of angiogenic inducers, such as VEGF, ANGPT2-mediated loosening of cell-matrix contacts may induce endothelial cell apoptosis with consequent vascular regression. In concert with VEGF, it may facilitate endothelial cell migration and proliferation, thus serving as a permissive angiogenic signal. {ECO:0000269|PubMed:15284220, ECO:0000269|PubMed:19116766, ECO:0000269|PubMed:19223473, ECO:0000269|PubMed:9204896}.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.230
RVIS EVS: -0.42
RVIS percentile EVS: 25.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.857

Gene Damage Prediction

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