UCP2

protein-coding

uncoupling protein 2, the group of Solute carrier family 25

Gene summary

Mitochondrial uncoupling proteins (UCP) are members of the larger family of mitochondrial anion carrier proteins (MACP). UCPs separate oxidative phosphorylation from ATP synthesis with energy dissipated as heat, also referred to as the mitochondrial proton leak. UCPs facilitate the transfer of anions from the inner to the outer mitochondrial membrane and the return transfer of protons from the outer to the inner mitochondrial membrane. They also reduce the mitochondrial membrane potential in mammalian cells. Tissue specificity occurs for the different UCPs and the exact methods of how UCPs transfer H+/OH- are not known. UCPs contain the three homologous protein domains of MACPs. This gene is expressed in many tissues, with the greatest expression in skeletal muscle. It is thought to play a role in nonshivering thermogenesis, obesity and diabetes. Chromosomal order is 5'-UCP3-UCP2-3'. [provided by RefSeq, Jul 2008]

Previous symbols:

BMIQ4

MANE transcript

NM_003355.3

Inheritance

ClinVar variants

U:84B:17

Top phenotype

hyperinsulinism due to UCP2 deficiency

gnomAD constraint

pLI —, LoF o/e 1.01

Max pathogenic AF

—

Genomic locus

chr11:73,974,061-73,982,843

External References & Databases

Ensembl (ENSG00000175567)

Transcript & Mutation Effects

hg38 • Region Span ~8.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperinsulinism due to UCP2 deficiencySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017183

Submitter: Orphanet

hyperinsulinism due to UCP2 deficiencyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0017183

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UCP2 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 72

not providedTotal: 57

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 4Total: 5

UCP2-related disorderTotal: 5

Maturity-onset diabetes of the young type 2Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003355.3. 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	1 clinvar	10
missense			73 clinvar	7 clinvar		80
nonsense			3 clinvar			3
start loss			1 clinvar			1
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	0	0	84	16	1	101

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003355.3	RefSeq	NP_003346.2	6	MANE Select
ENST00000663595.2	Ensembl	ENSP00000499695.1	6	MANE Select
NM_001381943.1	RefSeq	NP_001368872.1	6	Standard
NM_001381944.1	RefSeq	NP_001368873.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Electron Transport Chain
Energy Metabolism
The citric acid (TCA) cycle and respiratory electron transport
Metabolism
The fatty acid cycling model

Biological Process

response to superoxide
response to hypoxia
female pregnancy
aging
response to cold

Molecular Function

protein binding
oxidative phosphorylation uncoupler activity

Cellular Component

mitochondrion
mitochondrial inner membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000310473
Coding exons: 6
Length: 8641
Individuals with no LoFs: 125629
Homozygous LoFs: 1
Heterozygous LoFs: 118
Defined: 125748
p: 0.000473

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.00251	197	197	1.00	0.0000124	1985
Missense (PolyPhen)		60	66.092	0.90783		639
Synonymous	0.960	64	74.5	0.859	0.00000442	677
Loss of Function	-0.0391	15	14.8	1.01	0.00000109	132

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00041	0.00040	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00044	0.00044	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00059	0.00058	rare
South Asian	0.00078	0.00075	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: UCP are mitochondrial transporter proteins that create proton leaks across the inner mitochondrial membrane, thus uncoupling oxidative phosphorylation from ATP synthesis. As a result, energy is dissipated in the form of heat.;

Recessive Scores

pRec: 0.618

Intolerance Scores

LoFtool: 0.609
RVIS EVS: 0.11
RVIS percentile EVS: 61.91

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.573

Gene Damage Prediction

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