GPS2

protein-coding

G protein pathway suppressor 2, the group of NCoR/SMRT transcriptional repression complex subunits

Gene summary

This gene encodes a protein involved in G protein-mitogen-activated protein kinase (MAPK) signaling cascades. When overexpressed in mammalian cells, this gene could potently suppress a RAS- and MAPK-mediated signal and interfere with JNK activity, suggesting that the function of this gene may be signal repression. The encoded protein is an integral subunit of the NCOR1-HDAC3 (nuclear receptor corepressor 1-histone deacetylase 3) complex, and it was shown that the complex inhibits JNK activation through this subunit and thus could potentially provide an alternative mechanism for hormone-mediated antagonism of AP1 (activator protein 1) function. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004489.5

Inheritance

—

ClinVar variants

U:44

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr17:7,311,324-7,315,564

External References & Databases

Ensembl (ENSG00000132522)

Transcript & Mutation Effects

hg38 • Region Span ~4.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GPS2 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 29

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004489.5. 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			1 clinvar			1
missense			32 clinvar			32
nonsense			2 clinvar			2
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	0	0	44	0	0	44

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004489.5	RefSeq	NP_004480.1	10	MANE Select
ENST00000380728.7	Ensembl	ENSP00000370104.2	10	MANE Select
ENST00000389167.10	Ensembl	ENSP00000379841.4	10	Standard
ENST00000389167.9	Ensembl	ENSP00000379841.4	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

HTLV-I infection - Homo sapiens (human)
HDACs deacetylate histones
Chromatin modifying enzymes
Chromatin organization

Biological Process

negative regulation of transcription by RNA polymerase II
inactivation of MAPK activity
JNK cascade
negative regulation of tumor necrosis factor-mediated signaling pathway
positive regulation of cholesterol efflux

Molecular Function

transcription coactivator activity
transcription corepressor activity
GTPase inhibitor activity
protein binding
cyclin binding

Cellular Component

nucleus
nucleoplasm
mitochondrion
cytosol
transcriptional repressor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000380728
Coding exons: 10
Length: 4241
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.16	136	180	0.757	0.00000915	2122
Missense (PolyPhen)		19	17.715	1.0725		206
Synonymous	-4.48	111	65.1	1.71	0.00000321	623
Loss of Function	2.94	6	20.3	0.295	9.60e-7	228

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Key regulator of inflammation, lipid metabolism and mitochondrion homeostasis that acts by inhibiting the activity of the ubiquitin-conjugating enzyme UBE2N/Ubc13, thereby inhibiting 'Lys-63'-linked ubiquitination (By similarity). In the nucleus, can both acts as a corepressor and coactivator of transcription, depending on the context (PubMed:24943844). Acts as a transcription coactivator in adipocytes by promoting the recruitment of PPARG to promoters: acts by inhibiting the activity of the ubiquitin-conjugating enzyme UBE2N/Ubc13, leading to stabilization of KDM4A and subsequent histone H3 'Lys-9' (H3K9) demethylation (By similarity). Promotes cholesterol efflux by acting as a transcription coactivator (PubMed:19481530). Acts as a regulator of B-cell development by inhibiting UBE2N/Ubc13, thereby restricting the activation of Toll-like receptors (TLRs) and B- cell antigen receptors (BCRs) signaling pathways (By similarity). Acts as a key mediator of mitochondrial stress response: in response to mitochondrial depolarization, relocates from the mitochondria to the nucleus following desumoylation and specifically promotes expression of nuclear-encoded mitochondrial genes (PubMed:29499132). Promotes transcription of nuclear-encoded mitochondrial genes by inhibiting UBE2N/Ubc13 (PubMed:29499132). Can also act as a corepressor as part of the N-Cor repressor complex by repressing active PPARG (PubMed:19858209, PubMed:24943844). Plays an anti-inflammatory role in macrophages and is required for insulin sensitivity by acting as a corepressor (By similarity). Plays an anti-inflammatory role during the hepatic acute phase response by interacting with sumoylated NR1H2 and NR5A2 proteins, thereby preventing N-Cor corepressor complex dissociation (PubMed:20159957). In the cytosol, also plays a non- transcriptional role by regulating insulin signaling and pro- inflammatory pathways (By similarity). In the cytoplasm, acts as a negative regulator of inflammation by inhibiting the proinflammatory TNF-alpha pathway; acts by repressing UBE2N/Ubc13 activity (By similarity). In the cytoplasm of adipocytes, restricts the activation of insulin signaling via inhibition of UBE2N/Ubc13-mediated ubiquitination of AKT (By similarity). Able to suppress G-protein- and mitogen-activated protein kinase- mediated signal transduction (PubMed:8943324). Acts as a tumor- suppressor in liposarcoma (PubMed:27460081). {ECO:0000250|UniProtKB:Q921N8, ECO:0000269|PubMed:19481530, ECO:0000269|PubMed:19858209, ECO:0000269|PubMed:20159957, ECO:0000269|PubMed:24943844, ECO:0000269|PubMed:27460081, ECO:0000269|PubMed:29499132, ECO:0000269|PubMed:8943324}.;

Recessive Scores

pRec: 0.0705

Intolerance Scores

LoFtool: 0.499
RVIS EVS: -0.49
RVIS percentile EVS: 22.09

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.930

Gene Damage Prediction

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