ADRA2C

protein-coding

adrenoceptor alpha 2C, the group of Adrenoceptors

Gene summary

Alpha-2-adrenergic receptors are members of the G protein-coupled receptor superfamily. They include 3 highly homologous subtypes: alpha2A, alpha2B, and alpha2C. These receptors have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system. The mouse studies revealed that both the alpha2A and alpha2C subtypes were required for normal presynaptic control of transmitter release from sympathetic nerves in the heart and from central noradrenergic neurons. The alpha2A subtype inhibited transmitter release at high stimulation frequencies, whereas the alpha2C subtype modulated neurotransmission at lower levels of nerve activity. This gene encodes the alpha2C subtype, which contains no introns in either its coding or untranslated sequences. [provided by RefSeq, Jul 2008]

Previous symbols:

ADRA2L2
ADRA2RL2

MANE transcript

NM_000683.4

Inheritance

ClinVar variants

U:67B:11

Top phenotype

Beta-blocker response, association with

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr4:3,766,348-3,768,526

External References & Databases

Ensembl (ENSG00000184160)

Transcript & Mutation Effects

hg38 • Region Span ~2.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

Clinical Genomic Database (CGD)

Beta-blocker response, association withAD

Manifestation: General

Intervention: Pharmacogenomic

Rationale: The presence of variants may influence medication choice (eg, in congestive heart failure)

Refs: 17496726

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADRA2C variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 73

ADRA2C-related disorderTotal: 4

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000683.4. 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				9 clinvar		9
missense			67 clinvar	1 clinvar	1 clinvar	69
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	67	10	1	78

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000683.4	RefSeq	NP_000674.2	1	MANE Select
ENST00000330055.7	Ensembl	ENSP00000386069.2	1	MANE Select
ENST00000509482.1	Ensembl	ENSP00000426268.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neuroactive ligand-receptor interaction - Homo sapiens (human)
cGMP-PKG signaling pathway - Homo sapiens (human)
Sympathetic Nerve Pathway (Neuroeffector Junction)
GPCRs, Class A Rhodopsin-like
Monoamine GPCRs

Biological Process

G protein-coupled receptor signaling pathway
adenylate cyclase-modulating G protein-coupled receptor signaling pathway
cell-cell signaling
female pregnancy
negative regulation of norepinephrine secretion

Molecular Function

adrenergic receptor activity
alpha2-adrenergic receptor activity
protein binding
alpha-2A adrenergic receptor binding
protein homodimerization activity

Cellular Component

cytoplasm
endosome
plasma membrane
integral component of plasma membrane
axon terminus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000330055
Coding exons: 1
Length: 2177
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.64	161	231	0.696	0.0000118	2868
Missense (PolyPhen)		57	116.45	0.48946		1252
Synonymous	-0.652	118	109	1.08	0.00000579	1066
Loss of Function	2.41	2	10.4	0.192	4.51e-7	107

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	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Alpha-2 adrenergic receptors mediate the catecholamine- induced inhibition of adenylate cyclase through the action of G proteins.;

Recessive Scores

pRec: 0.0996

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.825

Gene Damage Prediction

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