ACKR2

protein-coding

atypical chemokine receptor 2, the group of Atypical chemokine receptors

Gene summary

This gene encodes a beta chemokine receptor, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. Chemokines and their receptor-mediated signal transduction are critical for the recruitment of effector immune cells to the inflammation site. This gene is expressed in a range of tissues and hemopoietic cells. The expression of this receptor in lymphatic endothelial cells and overexpression in vascular tumors suggested its function in chemokine-driven recirculation of leukocytes and possible chemokine effects on the development and growth of vascular tumors. This receptor appears to bind the majority of beta-chemokine family members; however, its specific function remains unknown. This gene is mapped to chromosome 3p21.3, a region that includes a cluster of chemokine receptor genes. [provided by RefSeq, Jul 2008]

Previous symbols:

CMKBR9
CCBP2

MANE transcript

NM_001296.5

Inheritance

—

ClinVar variants

U:12

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr3:42,804,752-42,887,974

External References & Databases

Ensembl (ENSG00000144648)

Transcript & Mutation Effects

hg38 • Region Span ~83.2 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 ACKR2 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 8

not providedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001296.5. 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						0
missense			11 clinvar			11
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	12	0	0	12

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001296.5	RefSeq	NP_001287.2	1	MANE Select
ENST00000422265.6	Ensembl	ENSP00000416996.1	1	MANE Select
ENST00000442925.5	Ensembl	ENSP00000396150.1	1	Standard
ENST00000442925.6	Ensembl	ENSP00000396150.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

GPCRs, Class A Rhodopsin-like

Biological Process

receptor-mediated endocytosis
chemotaxis
inflammatory response
immune response
G protein-coupled receptor signaling pathway

Molecular Function

chemokine receptor activity
scavenger receptor activity
C-C chemokine receptor activity
chemokine binding
C-C chemokine binding

Cellular Component

nucleoplasm
early endosome
cytosol
actin filament
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000422265
Coding exons: 1
Length: 83223
Individuals with no LoFs: 125710
Homozygous LoFs: 1
Heterozygous LoFs: 37
Defined: 125748
p: 0.000151

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.263	205	216	0.950	0.0000130	2525
Missense (PolyPhen)		67	61.346	1.0922		858
Synonymous	-0.0139	92	91.8	1.00	0.00000570	795
Loss of Function	0.712	5	7.04	0.710	3.08e-7	82

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00072	0.00069	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.00023	0.00023	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. Also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Acts as a receptor for chemokines including CCL2, CCL3, CCL3L1, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL17, CCL22, CCL23, CCL24, SCYA2/MCP-1, SCY3/MIP-1-alpha, SCYA5/RANTES and SCYA7/MCP-3. Upon active ligand stimulation, activates a beta-arrestin 1 (ARRB1)-dependent, G protein- independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin (CFL1) through a RAC1-PAK1- LIMK1 signaling pathway. Activation of this pathway results in up- regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. By scavenging chemokines in tissues, on the surfaces of lymphatic vessels, and in placenta, plays an essential role in the resolution (termination) of the inflammatory response and in the regulation of adaptive immune responses. Plays a major role in the immune silencing of macrophages during the resolution of inflammation. Acts as a regulator of inflammatory leukocyte interactions with lymphatic endothelial cells (LECs) and is required for immature/mature dendritic cells discrimination by LECs. {ECO:0000269|PubMed:23479571, ECO:0000269|PubMed:23633677}.;

Recessive Scores

pRec: 0.119

Intolerance Scores

RVIS EVS: 0.46
RVIS percentile EVS: 78.69

Essentials

Essential (CRISPR): N

Gene Damage Prediction

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