NR1D2
protein-codingnuclear receptor subfamily 1 group D member 2, the group of Nuclear receptor subfamily 1 group D
Gene summary
This gene encodes a member of the nuclear hormone receptor family, specifically the NR1 subfamily of receptors. The encoded protein functions as a transcriptional repressor and may play a role in circadian rhythms and carbohydrate and lipid metabolism. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~35.4 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 NR1D2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005126.5. 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 | 1 | 1 | 3 | ||
| missense | 1 | 71 | 3 | 75 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 0 | 1 | 76 | 4 | 1 | 82 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005117.3 | 8 | MANE Select | |
| Ensembl | ENSP00000310006.3 | 8 | MANE Select | |
| RefSeq | NP_001138897.1 | 7 | Standard | |
| Ensembl | ENSP00000373283.3 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- NHR
- Nuclear Receptors
- Exercise-induced Circadian Regulation
- Gene expression (Transcription)
- Generic Transcription Pathway
Biological Process
- negative regulation of transcription by RNA polymerase II
- regulation of transcription, DNA-templated
- transcription initiation from RNA polymerase II promoter
- multicellular organism development
- hormone-mediated signaling pathway
Molecular Function
- transcription regulatory region sequence-specific DNA binding
- RNA polymerase II regulatory region sequence-specific DNA binding
- RNA polymerase II proximal promoter sequence-specific DNA binding
- RNA polymerase II distal enhancer sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
Cellular Component
- nucleus
- nucleoplasm
- RNA polymerase II transcription factor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000312521
- Coding exons
- 8
- Length
- 35359
- Individuals with no LoFs
- 125732
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 15
- Defined
- 125747
- p
- 0.0000596
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.931 | 268 | 314 | 0.852 | 0.0000161 | 3899 |
| Missense (PolyPhen) | 64 | 111.78 | 0.57254 | 1332 | ||
| Synonymous | -1.13 | 120 | 105 | 1.14 | 0.00000516 | 1032 |
| Loss of Function | 2.93 | 8 | 23.2 | 0.344 | 0.00000126 | 296 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000088 | 0.000088 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components ARNTL/BMAL1 and CLOCK. Also regulates genes involved in metabolic functions, including lipid metabolism and the inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nuclegotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and also negatively regulates the expression of NR1D1. Regulates lipid and energy homeostasis in the skeletal muscle via repression of genes involved in lipid metabolism and myogenesis including: CD36, FABP3, FABP4, UCP3, SCD1 and MSTN. Regulates hepatic lipid metabolism via the repression of APOC3. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). In addition to its activity as a repressor, can also act as a transcriptional activator. Acts as a transcriptional activator of the sterol regulatory element-binding protein 1 (SREBF1) and the inflammatory mediator interleukin-6 (IL6) in the skeletal muscle. {ECO:0000269|PubMed:17892483, ECO:0000269|PubMed:17996965}.;
Recessive Scores
- pRec
- 0.158
Intolerance Scores
- LoFtool
- 0.121
- RVIS EVS
- 0.09
- RVIS percentile EVS
- 60.57
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.979
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |