NR2C2AP

Summary

NR2C2AP (nuclear receptor 2C2 associated protein, HGNC:30763) is a protein-coding gene on chromosome 19p13.11, encoding Nuclear receptor 2C2-associated protein (Q86WQ0). May act as a repressor of NR2C2-mediated transactivation by suppressing the binding between NR2C2/TR4 and the TR4-response element in target genes. It is a selective cancer dependency (DepMap: 42.8% of cell lines).

Located in nucleoplasm.

Source: NCBI Gene 126382 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 52 total
• Cancer dependency (DepMap): dependent in 42.8% of screened cell lines
• MANE Select transcript: NM_176880

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30763
Approved symbol	NR2C2AP
Name	nuclear receptor 2C2 associated protein
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	TRA16
Ensembl gene	ENSG00000184162
Ensembl biotype	protein_coding
OMIM	608719
Entrez	126382

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 11 protein_coding, 2 retained_intron

ENST00000331552, ENST00000420605, ENST00000537399, ENST00000538165, ENST00000539678, ENST00000539693, ENST00000544883, ENST00000892791, ENST00000892792, ENST00000926922, ENST00000926923, ENST00000926924, ENST00000943585

RefSeq mRNA: 2 — MANE Select: NM_176880 NM_001300945, NM_176880

CCDS: CCDS32967, CCDS74316

Canonical transcript exons

ENST00000331552 — 5 exons

Exon	Start	End
ENSE00001306819	19203023	19203414
ENSE00001503973	19201409	19202041
ENSE00003600185	19202331	19202398
ENSE00003694976	19202791	19202881
ENSE00003699019	19202470	19202575

Expression profiles

Bgee: expression breadth ubiquitous, 217 present calls, max score 90.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.4161 / max 60.3231, expressed in 1698 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180130	7.5420	1678
180129	0.8741	494

Top tissues by expression

241 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	90.14	gold quality
mucosa of transverse colon	UBERON:0004991	88.68	gold quality
tendon of biceps brachii	UBERON:0008188	87.69	gold quality
granulocyte	CL:0000094	87.04	gold quality
oviduct epithelium	UBERON:0004804	86.97	gold quality
skin of abdomen	UBERON:0001416	86.96	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.88	gold quality
lower esophagus	UBERON:0013473	86.86	gold quality
skin of leg	UBERON:0001511	86.81	gold quality
lower esophagus mucosa	UBERON:0035834	86.64	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.54	gold quality
esophagus	UBERON:0001043	85.75	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	85.59	gold quality
left ovary	UBERON:0002119	85.53	gold quality
muscle layer of sigmoid colon	UBERON:0035805	85.42	gold quality
esophagus mucosa	UBERON:0002469	85.28	gold quality
body of uterus	UBERON:0009853	84.97	gold quality
body of pancreas	UBERON:0001150	84.96	gold quality
body of stomach	UBERON:0001161	84.92	gold quality
ectocervix	UBERON:0012249	84.86	gold quality
popliteal artery	UBERON:0002250	84.75	gold quality
tibial artery	UBERON:0007610	84.74	gold quality
right uterine tube	UBERON:0001302	84.72	gold quality
islet of Langerhans	UBERON:0000006	84.68	gold quality
zone of skin	UBERON:0000014	84.58	gold quality
right ovary	UBERON:0002118	84.49	gold quality
vermiform appendix	UBERON:0001154	84.36	gold quality
endocervix	UBERON:0000458	84.27	gold quality
transverse colon	UBERON:0001157	84.25	gold quality
minor salivary gland	UBERON:0001830	84.21	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.26

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

58 targeting NR2C2AP, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-520A-5P	99.35	66.72	1632

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 42.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• TRA16 may function as a novel repressor to selectively suppress the TR4-mediated transactivation (PMID:12486131)
• Together, these findings provide the first in vivo evidence that an orphan nuclear receptor, such as TR4, may play major roles in the RA-mediated apoptosis or differentiation in P19 cells. (PMID:15381082)
• Taken together, these results suggested that TR4 should be one of important regulators of OXT gene expression. (PMID:17054912)
• High TRA16 expression promotes small cell lung carcinoma by activating estrogen receptor beta and blocking testicular orphan nuclear receptor 2 (PMID:23129017)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nr2c2ap	ENSDARG00000056162
mus_musculus	Nr2c2ap	ENSMUSG00000071078
rattus_norvegicus	Nr2c2ap	ENSRNOG00000022247
drosophila_melanogaster	CG34213	FBGN0085242

Protein

Protein identifiers

Nuclear receptor 2C2-associated protein — Q86WQ0 (reviewed: Q86WQ0)

Alternative names: TR4 orphan receptor-associated 16 kDa protein

All UniProt accessions (4): F5H0B6, Q86WQ0, U3KQ53, U3KQN8

UniProt curated annotations — full annotation on UniProt →

Function. May act as a repressor of NR2C2-mediated transactivation by suppressing the binding between NR2C2/TR4 and the TR4-response element in target genes.

Subunit / interactions. Interacts with NR2C2/TR4.

Subcellular location. Nucleus.

Tissue specificity. Expressed in all tissues examined, with highest expression in heart, skeletal muscle and pancreas.

Similarity. Belongs to the NR2C2AP family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q86WQ0-1	1	yes
Q86WQ0-2	2

RefSeq proteins (2): NP_001287874, NP_795361* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008979	Galactose-bd-like_sf	Homologous_superfamily

UniProt features (2 total): chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86WQ0-F1	96.58	0.97

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-383280	Nuclear Receptor transcription pathway

MSigDB gene sets: 76 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, CHANDRAN_METASTASIS_DN, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, SLEBOS_HEAD_AND_NECK_CANCER_WITH_HPV_UP, ACEVEDO_LIVER_CANCER_UP, NUYTTEN_EZH2_TARGETS_DN, chr19p13, CCTGAGT_MIR510, DUTERTRE_ESTRADIOL_RESPONSE_6HR_UP, DUTERTRE_ESTRADIOL_RESPONSE_24HR_UP, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_QTL_TRANS, CCTNTMAGA_UNKNOWN, MYC_UP.V1_UP, NFE2L1_TARGET_GENES, ZFP91_TARGET_GENES

GO Biological Process (0):

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (2): nucleoplasm (GO:0005654), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	1
nuclear lumen	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

964 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NR2C2AP	NR2C2	P49116	854
NR2C2AP	SUGP1	Q8IWZ8	533
NR2C2AP	RFXANK	O14593	529
NR2C2AP	SLC35E1	Q96K37	525
NR2C2AP	DDX49	Q9Y6V7	495
NR2C2AP	CIB3	Q96Q77	494
NR2C2AP	CHERP	Q8IWX8	491
NR2C2AP	SLC25A42	Q86VD7	489
NR2C2AP	FAM194C	Q8ND61	447
NR2C2AP	YJEFN3	A6XGL0	432
NR2C2AP	ZBTB3	Q9H5J0	413
NR2C2AP	SGPP1	Q9BX95	389
NR2C2AP	SYDE2	Q5VT97	366
NR2C2AP	NCOA5	Q9HCD5	353
NR2C2AP	TPGS2	Q68CL5	344

IntAct

32 interactions, top by confidence:

A	B	Type	Score
NR2C2	NR2C2AP	psi-mi:“MI:0915”(physical association)	0.620
NR2C2AP	SLC16A3	psi-mi:“MI:0915”(physical association)	0.560
TCF4	NR2C2AP	psi-mi:“MI:0915”(physical association)	0.560
NR2C2AP	REL	psi-mi:“MI:0915”(physical association)	0.560
SLC16A3	NR2C2AP	psi-mi:“MI:0915”(physical association)	0.560
REL	NR2C2AP	psi-mi:“MI:0915”(physical association)	0.560
NR2C2AP	TCF4	psi-mi:“MI:0915”(physical association)	0.560
NR2C2AP	TEPSIN	psi-mi:“MI:0915”(physical association)	0.560
NR2C2AP	VPS52	psi-mi:“MI:0915”(physical association)	0.560
NR2C2AP	DDIT4L	psi-mi:“MI:0915”(physical association)	0.560
HTT	NR2C2AP	psi-mi:“MI:0915”(physical association)	0.560
NR2C2	NR2C2AP	psi-mi:“MI:0403”(colocalization)	0.460
NR2C2	NR2C2AP	psi-mi:“MI:0915”(physical association)	0.460
NR2C2	NR2C2	psi-mi:“MI:0915”(physical association)	0.370
NR2C2AP	VPS52	psi-mi:“MI:0915”(physical association)	0.000
NR2C2AP	REL	psi-mi:“MI:0915”(physical association)	0.000
NR2C2AP	DDIT4L	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): NR2C2AP (Two-hybrid), NR2C2AP (Two-hybrid), NR2C2AP (Two-hybrid), NR2C2AP (Co-fractionation), NR2C2AP (Two-hybrid), NR2C2AP (Two-hybrid), NR2C2AP (Two-hybrid), VPS52 (Two-hybrid), NR2C2 (Two-hybrid), NR2C2 (Reconstituted Complex), NR2C2 (Affinity Capture-Western), NR2C2AP (Negative Genetic), NR2C2AP (Negative Genetic), NR2C2AP (Negative Genetic), NR2C2AP (Two-hybrid)

ESM2 similar proteins: A1L1F0, A4IFG2, A5A6P1, A5GFY8, C3K0A7, D9IVE5, O43175, P10688, P10895, P18407, P25335, Q01415, Q02JZ8, Q09913, Q0V9A9, Q1ED21, Q2KIG4, Q32NH8, Q3B8C3, Q3KFK9, Q3TV70, Q48KS4, Q4K8H3, Q4R964, Q4ZVG8, Q58DU8, Q5EAD2, Q5PQR3, Q5R6J8, Q5R7M2, Q61753, Q640T1, Q68FH4, Q6AYP0, Q6DGA6, Q6LPX9, Q86WQ0, Q87YX4, Q8BIP0, Q8C726

Diamond homologs: A1L1F0, Q1ED21, Q3B8C3, Q3TV70, Q58DU8, Q86WQ0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

52 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	12
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

750 predictions. Top by Δscore:

Variant	Effect	Δscore
19:19201647:A:AG	acceptor_gain	1.0000
19:19201648:G:GG	acceptor_gain	1.0000
19:19202472:T:TA	donor_gain	1.0000
19:19201643:T:G	acceptor_gain	0.9900
19:19201645:TCAGT:T	acceptor_loss	0.9900
19:19201647:A:C	acceptor_loss	0.9900
19:19201647:AGT:A	acceptor_gain	0.9900
19:19201648:GT:G	acceptor_gain	0.9900
19:19201648:GTG:G	acceptor_gain	0.9900
19:19201648:GTGC:G	acceptor_gain	0.9900
19:19201648:GTGCA:G	acceptor_gain	0.9900
19:19202023:CAG:C	acceptor_gain	0.9900
19:19202026:C:CC	acceptor_gain	0.9900
19:19202029:G:GC	acceptor_gain	0.9900
19:19202574:CC:C	acceptor_gain	0.9900
19:19202575:CC:C	acceptor_gain	0.9900
19:19202576:C:CC	acceptor_gain	0.9900
19:19202577:T:C	acceptor_loss	0.9900
19:19202786:CTCA:C	donor_loss	0.9900
19:19202788:CACCT:C	donor_loss	0.9900
19:19202789:ACCT:A	donor_loss	0.9900
19:19202790:C:CT	donor_loss	0.9900
19:19202892:C:CT	acceptor_gain	0.9900
19:19202892:C:T	acceptor_gain	0.9900
19:19202893:A:T	acceptor_gain	0.9900
19:19202898:C:CT	acceptor_gain	0.9900
19:19202899:A:T	acceptor_gain	0.9900
19:19201636:T:TA	acceptor_gain	0.9800
19:19201642:A:AG	acceptor_gain	0.9800
19:19202029:G:C	acceptor_gain	0.9800

AlphaMissense

907 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:19202495:G:C	F70L	0.994
19:19202495:G:T	F70L	0.994
19:19202497:A:G	F70L	0.994
19:19202805:A:G	W39R	0.994
19:19202805:A:T	W39R	0.994
19:19202803:C:A	W39C	0.988
19:19202803:C:G	W39C	0.988
19:19202875:A:C	S15R	0.987
19:19202875:A:T	S15R	0.987
19:19202877:T:G	S15R	0.987
19:19202507:A:C	F66L	0.986
19:19202507:A:T	F66L	0.986
19:19202509:A:G	F66L	0.986
19:19201968:C:G	R126P	0.985
19:19202804:C:G	W39S	0.983
19:19201969:G:T	R126S	0.981
19:19201950:A:G	L132P	0.976
19:19202007:A:G	L113P	0.974
19:19202496:A:G	F70S	0.972
19:19201973:A:C	F124L	0.968
19:19201973:A:T	F124L	0.968
19:19201975:A:G	F124L	0.968
19:19202799:A:G	S41P	0.968
19:19202508:A:G	F66S	0.967
19:19202520:A:G	L62P	0.966
19:19201957:A:C	Y130D	0.963
19:19202553:A:G	L51P	0.961
19:19201971:C:A	G125V	0.958
19:19202546:A:C	F53L	0.957
19:19202546:A:T	F53L	0.957

dbSNP variants (sampled 300 via entrez): RS1001368041 (19:19201045 C>A,T), RS1003846048 (19:19202827 G>C,T), RS1004475849 (19:19204409 G>A,T), RS1004616283 (19:19204218 C>T), RS1005382287 (19:19202947 G>A), RS1005759170 (19:19203321 A>G), RS1006396261 (19:19201836 C>G), RS1008179056 (19:19204576 G>A), RS1008190402 (19:19204885 G>A,T), RS1009464812 (19:19202272 G>A,C,T), RS1010472683 (19:19205197 G>A,C), RS1011135747 (19:19203520 G>A,C), RS1011393991 (19:19204115 G>A,C), RS1012425243 (19:19204436 A>G), RS1012744187 (19:19203683 A>G,T)

Disease associations

OMIM: gene MIM:608719 | disease phenotypes: MIM:209920

GenCC curated gene-disease

Mondo (1): MHC class II deficiency (MONDO:0008855)

Orphanet (1): Immunodeficiency by defective expression of MHC class II (Orphanet:572)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST008103_10	Bipolar disorder	1.000000e-09
GCST008115_2	Bipolar I disorder	3.000000e-09
GCST008116_4	Bipolar II disorder	4.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009963	bipolar I disorder
EFO:0009964	bipolar II disorder

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537079	Bare lymphocyte syndrome 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	2
potassium chromate(VI)	affects cotreatment, decreases expression	2
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	2
Valproic Acid	increases expression, increases methylation	2
manganese chloride	affects cotreatment, increases abundance, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
perfluoro-n-nonanoic acid	increases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Calcitriol	decreases expression, affects cotreatment	1
Cisplatin	increases expression	1
Coumestrol	increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Methyl Methanesulfonate	increases expression	1
Smoke	decreases expression	1
Testosterone	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

3 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT04251325	Not specified	UNKNOWN	Socio-demographic Characteristics of Basic Life Support Course Participants
NCT04353089	Not specified	UNKNOWN	Geographical Association Between Basic Life Support Courses, Bystander Cardiopulmonary Resuscitation and Survival