MC1R

protein-coding

melanocortin 1 receptor, the group of Melanocortin receptors

Gene summary

This intronless gene encodes the receptor protein for melanocyte-stimulating hormone (MSH). The encoded protein, a seven pass transmembrane G protein coupled receptor, controls melanogenesis. Two types of melanin exist: red pheomelanin and black eumelanin. Gene mutations that lead to a loss in function are associated with increased pheomelanin production, which leads to lighter skin and hair color. Eumelanin is photoprotective but pheomelanin may contribute to UV-induced skin damage by generating free radicals upon UV radiation. Binding of MSH to its receptor activates the receptor and stimulates eumelanin synthesis. This receptor is a major determining factor in sun sensitivity and is a genetic risk factor for melanoma and non-melanoma skin cancer. Over 30 variant alleles have been identified which correlate with skin and hair color, providing evidence that this gene is an important component in determining normal human pigment variation. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002386.4

Inheritance

AR, AD

ClinVar variants

P:2U:460B:298

Top phenotype

Increased analgesia from kappa-opioid receptor agonist, female specific

gnomAD constraint

pLI —, LoF o/e 1.97

Max pathogenic AF

—

Genomic locus

chr16:89,912,119-89,920,973

External References & Databases

Ensembl (ENSG00000258839)

Transcript & Mutation Effects

hg38 • Region Span ~8.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

oculocutaneous albinism type 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008746

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Increased analgesia from kappa-opioid receptor agonist, female specificAD

Manifestation: General

Intervention: Pharmacogenomic

Rationale: Variants may have pharmacogenomic relevance, as results suggest that women with 2 variant MC1R alleles demonstrate greater analgesia from kappa-opioid pentazocine

Comments: Skin/hair/eye pigmentation, variation in may not have actionable relevance, though there may be increased risk of skin cancer

Refs: 7581459; 8894704; 11030758; 10631149; 11487574; 11500805; 11500806; 12876664; 12839583; 12663858; 16809487; 17952075; 19578364; 21693730; 21128237; 22095472; 22561518

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MC1R variants in ClinVar

15 Conditions Cataloged

not specifiedTotal: 491

Melanoma, cutaneous malignant, susceptibility to, 5Total: 438

not providedTotal: 51

Tyrosinase-positive oculocutaneous albinismTotal: 33

SKIN/HAIR/EYE PIGMENTATION, VARIATION IN, 2Total: 27

Increased analgesia from kappa-opioid receptor agonist, female-specificTotal: 23

MC1R-related disorderTotal: 9

Skin and Hair HypopigmentationTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002386.4. 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			7 clinvar	251 clinvar	2 clinvar	260
missense			417 clinvar	42 clinvar	2 clinvar	461
nonsense		1 clinvar	11 clinvar	1 clinvar		13
start loss			1 clinvar			1
frameshift		1 clinvar	24 clinvar			25
splice donor/acceptor (+/-2bp)						0
Total	0	2	460	294	4	760

Highest pathogenic variant AF is 0.0000068162103

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002386.4	RefSeq	NP_002377.4	1	MANE Select
ENST00000555147.2	Ensembl	ENSP00000451605.1	1	MANE Select
ENST00000555427.1	Ensembl	ENSP00000451760.1	2	Standard
ENST00000639847.1	Ensembl	ENSP00000492011.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neuroactive ligand-receptor interaction - Homo sapiens (human)
Melanogenesis - Homo sapiens (human)
Peptide GPCRs
GPCRs, Class A Rhodopsin-like
Signaling by GPCR

Biological Process

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
multicellular organism development
UV protection

Molecular Function

melanocortin receptor activity
melanocyte-stimulating hormone receptor activity
protein binding
G protein-coupled peptide receptor activity
ubiquitin protein ligase binding

Cellular Component

plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000555147
Coding exons: 1
Length: 8859
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	-2.34	299	205	1.46	0.0000141	2000
Missense (PolyPhen)		98	54.866	1.7862		702
Synonymous	-3.14	146	105	1.39	0.00000820	720
Loss of Function	-2.21	12	6.10	1.97	3.47e-7	58

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: Receptor for MSH (alpha, beta and gamma) and ACTH. The activity of this receptor is mediated by G proteins which activate adenylate cyclase.;
Disease: DISEASE: Melanoma, cutaneous malignant 5 (CMM5) [MIM:613099]: A malignant neoplasm of melanocytes, arising de novo or from a pre- existing benign nevus, which occurs most often in the skin but also may involve other sites. {ECO:0000269|PubMed:17434924, ECO:0000269|PubMed:19338054}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.689

Intolerance Scores

RVIS EVS: 0.34
RVIS percentile EVS: 73.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.781

Gene Damage Prediction

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