NCOA2
protein-codingnuclear receptor coactivator 2, the group of Lysine acetyltransferases|PAS domain containing|Basic helix-loop-helix proteins
Gene summary
The protein encoded by this gene functions as a transcriptional coactivator for nuclear hormone receptors, including steroid, thyroid, retinoid, and vitamin D receptors. The encoded protein acts as an intermediary factor for the ligand-dependent activity of these nuclear receptors, which regulate their target genes upon binding of cognate response elements. This gene has been found to be involved in translocations that result in fusions with other genes in various cancers, including the lysine acetyltransferase 6A (KAT6A) gene in acute myeloid leukemia, the ETS variant 6 (ETV6) gene in acute lymphoblastic leukemia, and the hes related family bHLH transcription factor with YRPW motif 1 (HEY1) gene in mesenchymal chondrosarcoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~294.0 kbGenCC 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 NCOA2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006540.4. 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 | 4 | 4 | 2 | 10 | ||
| missense | 181 | 4 | 185 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 0 | 0 | 189 | 8 | 2 | 199 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006531.1 | 21 | MANE Select | |
| Ensembl | ENSP00000399968.2 | 21 | MANE Select | |
| RefSeq | NP_001308632.1 | 21 | Standard | |
| RefSeq | NP_001308636.1 | 21 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ncoa2 | Danio rerio | Structure: intersegmental vessel Quality: aplastic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Thyroid hormone signaling pathway - Homo sapiens (human)
- Estrogen signaling pathway - Homo sapiens (human)
- Androgen receptor signaling pathway
- Corticotropin-releasing hormone signaling pathway
- Adipogenesis
Biological Process
- negative regulation of transcription by RNA polymerase II
- regulation of transcription, DNA-templated
- regulation of glucose metabolic process
- bile acid and bile salt transport
- regulation of lipid metabolic process
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding
- chromatin binding
- transcription coactivator activity
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- nuclear body
- protein-containing complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000452400
- Coding exons
- 21
- Length
- 294044
- Individuals with no LoFs
- 124649
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 124654
- p
- 0.0000201
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.29 | 622 | 805 | 0.773 | 0.0000422 | 9734 |
| Missense (PolyPhen) | 128 | 234.63 | 0.54553 | 2971 | ||
| Synonymous | 0.755 | 274 | 290 | 0.944 | 0.0000161 | 2786 |
| Loss of Function | 7.06 | 3 | 63.9 | 0.0469 | 0.00000317 | 731 |
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 | 0.000056 | 0.000056 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF- 2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues. Critical regulator of glucose metabolism regulation, acts as RORA coactivator to specifically modulate G6PC expression. Involved in the positive regulation of the transcriptional activity of the glucocorticoid receptor NR3C1 by sumoylation enhancer RWDD3. Positively regulates the circadian clock by acting as a transcriptional coactivator for the CLOCK- ARNTL/BMAL1 heterodimer (By similarity). {ECO:0000250|UniProtKB:Q61026, ECO:0000269|PubMed:23508108, ECO:0000269|PubMed:9430642}.;
- Disease
- DISEASE: Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N- terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation. {ECO:0000269|PubMed:12676584, ECO:0000269|PubMed:15657427, ECO:0000269|PubMed:9558366}.;
Recessive Scores
- pRec
- 0.317
Intolerance Scores
- RVIS EVS
- -1.03
- RVIS percentile EVS
- 7.86
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |