MC2R

protein-coding

melanocortin 2 receptor, the group of Melanocortin receptors

Gene summary

MC2R encodes one member of the five-member G-protein associated melanocortin receptor family. Melanocortins (melanocyte-stimulating hormones and adrenocorticotropic hormone) are peptides derived from pro-opiomelanocortin (POMC). MC2R is selectively activated by adrenocorticotropic hormone, whereas the other four melanocortin receptors recognize a variety of melanocortin ligands. Mutations in MC2R can result in familial glucocorticoid deficiency. Alternate transcript variants have been found for this gene. [provided by RefSeq, May 2014]

MANE transcript

NM_000529.2

Inheritance

ClinVar variants

P:39U:47B:16

Top phenotype

Glucocorticoid deficiency 1

gnomAD constraint

pLI —, LoF o/e 1.08

Max pathogenic AF

—

Genomic locus

chr18:13,882,044-13,915,707

External References & Databases

Ensembl (ENSG00000185231)

Transcript & Mutation Effects

hg38 • Region Span ~33.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glucocorticoid deficiency 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024536

Submitter: G2P

familial glucocorticoid deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008733

Submitter: Orphanet

glucocorticoid deficiency 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024536

Submitter: PanelApp Australia

glucocorticoid deficiency 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024536

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Glucocorticoid deficiency 1AR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: Early recognition and preventive measures and treatment related to hypoglycemia (as well as to potential infectious episodes) can be effective

Refs: 13616862; 4302512; 4312011; 4342294; 4349230; 238474; 2539720; 8094489; 8227361; 7627261; 12851305; 21823545; 22337906; 22814974

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MC2R variants in ClinVar

7 Conditions Cataloged

Glucocorticoid deficiency 1Total: 49

Inborn genetic diseasesTotal: 36

not providedTotal: 25

Glucocorticoid DeficiencyTotal: 11

MC2R-related disordersTotal: 7

MC2R-related disorderTotal: 5

not specifiedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000529.2. 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			3 clinvar	9 clinvar		12
missense	11 clinvar	13 clinvar	44 clinvar	6 clinvar	1 clinvar	75
nonsense	2 clinvar	3 clinvar				5
start loss						0
frameshift	4 clinvar	6 clinvar				10
splice donor/acceptor (+/-2bp)						0
Total	17	22	47	15	1	102

Highest pathogenic variant AF is 0.00045848254

Loading ClinVar variants...

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_000529.2	RefSeq	NP_000520.1	1	MANE Select
ENST00000327606.4	Ensembl	ENSP00000333821.2	1	MANE Select
NM_001291911.1	RefSeq	NP_001278840.1	1	Standard
ENST00000399821.2	Ensembl	ENSP00000382718.2	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cortisol synthesis and secretion - Homo sapiens (human)
Aldosterone synthesis and secretion - Homo sapiens (human)
Cushing,s syndrome - Homo sapiens (human)
cAMP signaling pathway - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)

Biological Process

placenta development
G protein-coupled receptor signaling pathway
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger
adenylate cyclase-activating G protein-coupled receptor signaling pathway
neuropeptide signaling pathway

Molecular Function

melanocortin receptor activity
corticotropin receptor activity
protein binding

Cellular Component

cytoplasm
plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000327606
Coding exons: 1
Length: 33664
Individuals with no LoFs: 125721
Homozygous LoFs: 0
Heterozygous LoFs: 24
Defined: 125745
p: 0.0000954

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.00651	174	174	0.999	0.0000107	1974
Missense (PolyPhen)		58	69.001	0.84056		842
Synonymous	-1.04	85	73.6	1.15	0.00000506	609
Loss of Function	-0.156	5	4.64	1.08	2.63e-7	60

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.000065	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for corticotropin (ACTH). This receptor is mediated by G proteins (G(s)) which activate adenylate cyclase (cAMP). {ECO:0000269|PubMed:19329486, ECO:0000269|PubMed:20371771}.;

Recessive Scores

pRec: 0.524

Intolerance Scores

LoFtool: 0.371
RVIS EVS: 0.26
RVIS percentile EVS: 70.44

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.210

Gene Damage Prediction

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