MRAP

protein-coding

melanocortin 2 receptor accessory protein

Gene summary

This gene encodes a melanocortin receptor-interacting protein. The encoded protein regulates trafficking and function of the melanocortin 2 receptor in the adrenal gland. The encoded protein can also modulate signaling of other melanocortin receptors. Mutations in this gene have been associated with familial glucocorticoid deficiency type 2. Alternatively spliced transcript variants have been described. [provided by RefSeq, Dec 2009]

Previous symbols:

C21orf61

MANE transcript

NM_001379228.1

Inheritance

ClinVar variants

P:8U:38B:15

Top phenotype

Glucocorticoid deficiency 2

gnomAD constraint

pLI —, LoF o/e 0.91

Max pathogenic AF

—

Genomic locus

chr21:32,291,813-32,314,784

External References & Databases

Ensembl (ENSG00000170262)

Transcript & Mutation Effects

hg38 • Region Span ~23.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glucocorticoid deficiency 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011826

Submitter: G2P

glucocorticoid deficiency 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011826

Submitter: Labcorp Genetics (formerly Invitae)

glucocorticoid deficiency 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011826

Submitter: PanelApp Australia

familial glucocorticoid deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008733

Submitter: Orphanet

Clinical Genomic Database (CGD)

Glucocorticoid deficiency 2AR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: Cortisol treatment can be effective to pevent manifestations such as hypoglycemia or severe sequelae of infectious episodes in infancy/childhood

Refs: 15654338; 16868047; 20427498; 21951701

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MRAP variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 35

Glucocorticoid deficiency 2Total: 23

not providedTotal: 11

MRAP-related disorderTotal: 7

Glucocorticoid deficiency 1Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001379228.1. 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	4 clinvar	3 clinvar	10
missense			33 clinvar	6 clinvar	2 clinvar	41
nonsense						0
start loss	2 clinvar					2
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)	5 clinvar		1 clinvar			6
Total	8	0	38	10	5	61

Highest pathogenic variant AF is 0.00008305391

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_001379228.1	RefSeq	NP_001366157.1	3	MANE Select
ENST00000303645.10	Ensembl	ENSP00000306697.5	3	MANE Select
NM_001285394.2	RefSeq	NP_001272323.1	2	Standard
NM_178817.4	RefSeq	NP_848932.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cortisol synthesis and secretion - Homo sapiens (human)
Cushing,s syndrome - Homo sapiens (human)

Biological Process

protein localization to plasma membrane
positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
negative regulation of protein localization to plasma membrane

Molecular Function

protein binding
corticotropin hormone receptor binding
type 3 melanocortin receptor binding
type 4 melanocortin receptor binding
type 5 melanocortin receptor binding

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000399784
Coding exons: 3
Length: 22972
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 125748
p: 0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0747	103	101	1.02	0.00000580	1113
Missense (PolyPhen)		31	25.77	1.203		314
Synonymous	-1.16	58	47.8	1.21	0.00000334	350
Loss of Function	0.176	4	4.40	0.909	2.87e-7	44

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.0011	0.0011	notable
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Modulator of melanocortin receptors (MC1R, MC2R, MC3R, MC4R and MC5R). Acts by increasing ligand-sensitivity of melanocortin receptors and enhancing generation of cAMP by the receptors. Required both for MC2R trafficking to the cell surface of adrenal cells and for signaling in response to corticotropin (ACTH). May be involved in the intracellular trafficking pathways in adipocyte cells. {ECO:0000269|PubMed:15654338, ECO:0000269|PubMed:19329486, ECO:0000269|PubMed:20371771}.;

Recessive Scores

pRec: 0.357

Intolerance Scores

LoFtool: 0.348
RVIS EVS: 0.37
RVIS percentile EVS: 75.29

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.313

Gene Damage Prediction

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