GRK2

protein-coding

G protein-coupled receptor kinase 2, the group of AGC family kinases|Pleckstrin homology domain containing

Gene summary

This gene encodes a member of the G protein-coupled receptor kinase family of proteins. The encoded protein phosphorylates the beta-adrenergic receptor as well as a wide range of other substrates including non-GPCR cell surface receptors, and cytoskeletal, mitochondrial, and transcription factor proteins. Data from rodent models supports a role for this gene in embryonic development, heart function and metabolism. Elevated expression of this gene has been observed in human patients with heart failure and Alzheimer's disease. [provided by RefSeq, Sep 2017]

Previous symbols:

ADRBK1

MANE transcript

NM_001619.5

Inheritance

ClinVar variants

P:3U:22B:4

Top phenotype

Jeune thoracic dystrophy

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr11:67,266,473-67,286,556

External References & Databases

Ensembl (ENSG00000173020)

Transcript & Mutation Effects

hg38 • Region Span ~20.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Jeune syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0018770

Submitter: PanelApp Australia

Jeune syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0018770

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRK2 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 8

not specifiedTotal: 5

Jeune thoracic dystrophyTotal: 3

Jeune syndrome - GRK2-relatedTotal: 1

GRK2-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001619.5. 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	1 clinvar	4
missense	1 clinvar		11 clinvar	1 clinvar		13
nonsense						0
start loss						0
frameshift		1 clinvar	1 clinvar			2
splice donor/acceptor (+/-2bp)		1 clinvar	9 clinvar			10
Total	1	2	22	3	1	29

Highest pathogenic variant AF is 0.0000013682848

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001619.5	RefSeq	NP_001610.2	21	MANE Select
ENST00000308595.10	Ensembl	ENSP00000312262.5	21	MANE Select
ENST00000526285.1	Ensembl	ENSP00000434126.1	14	Standard
ENST00000526285.2	Ensembl	ENSP00000434126.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glutamatergic synapse - Homo sapiens (human)
Endocytosis - Homo sapiens (human)
Chemokine signaling pathway - Homo sapiens (human)
Olfactory transduction - Homo sapiens (human)
Morphine addiction - Homo sapiens (human)

Biological Process

desensitization of G protein-coupled receptor signaling pathway
negative regulation of the force of heart contraction by chemical signal
G protein-coupled receptor signaling pathway
G protein-coupled acetylcholine receptor signaling pathway
tachykinin receptor signaling pathway

Molecular Function

protein kinase activity
G protein-coupled receptor kinase activity
protein binding
ATP binding
alpha-2A adrenergic receptor binding

Cellular Component

cytoplasm
cytosol
plasma membrane
cilium
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000308595
Coding exons: 21
Length: 20147
Individuals with no LoFs: 125654
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125658
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.22	254	445	0.571	0.0000306	4536
Missense (PolyPhen)		73	174.8	0.41762		1743
Synonymous	-1.03	205	187	1.10	0.0000136	1269
Loss of Function	5.70	3	43.7	0.0687	0.00000224	479

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	0.000046	0.000046	rare
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them. Key regulator of LPAR1 signaling. Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor. Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner (PubMed:19306925, PubMed:19715378). Positively regulates ciliary smoothened (SMO)- dependent Hedgehog (Hh) signaling pathway by faciltating the trafficking of SMO into the cilium and the stimulation of SMO activity (By similarity). {ECO:0000250|UniProtKB:P21146, ECO:0000269|PubMed:19306925, ECO:0000269|PubMed:19715378}.;

Recessive Scores

pRec: 0.452

Intolerance Scores

RVIS EVS: -1.16
RVIS percentile EVS: 6.17

Essentials

Essential (gene trap): N