ID2
protein-codinginhibitor of DNA binding 2, the group of Basic helix-loop-helix proteins
Gene summary
The protein encoded by this gene belongs to the inhibitor of DNA binding family, members of which are transcriptional regulators that contain a helix-loop-helix (HLH) domain but not a basic domain. Members of the inhibitor of DNA binding family inhibit the functions of basic helix-loop-helix transcription factors in a dominant-negative manner by suppressing their heterodimerization partners through the HLH domains. This protein may play a role in negatively regulating cell differentiation. A pseudogene of this gene is located on chromosome 3. [provided by RefSeq, Aug 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~5.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: ClinGen
To date, *ID2* has not been reported in relation to congenital heart disease in humans. One missense mutation in ID2 was reported in a human causing developmental and epileptic encephalopathy, however the congenital heart phenotype was not mentioned (PMID: 31175295). The mechanism of disease is unknown. This gene-disease relationship is supported by two expression studies in the heart (PMID: 15472070, 17604724), and one mouse model that exhibits features of congenital heart disease including atrioventricular septal defect (PMID: 21330551). In summary, the evidence to support the gene-disease relationship between ID2 and congenital heart disease is disputed. More evidence is needed to either support or entirely refute the role ID2 plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 11/27/2023 (SOP Version 10)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ID2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002166.5. 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 | ||||
| missense | 23 | 23 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 23 | 0 | 1 | 24 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002157.2 | 2 | MANE Select | |
| Ensembl | ENSP00000379585.1 | 2 | MANE Select | |
| Ensembl | ENSP00000234091.4 | 2 | Standard | |
| Ensembl | ENSP00000385465.2 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| id2a | Danio rerio | Structure: retinal bipolar neuron Quality: absent abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- TGF-beta signaling pathway - Homo sapiens (human)
- Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
- Hippo signaling pathway - Homo sapiens (human)
- Transcriptional misregulation in cancer - Homo sapiens (human)
- miRs in Muscle Cell Differentiation
Biological Process
- negative regulation of transcription by RNA polymerase II
- metanephros development
- natural killer cell differentiation
- thigmotaxis
- membranous septum morphogenesis
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- RNA polymerase II transcription factor binding
- DNA-binding transcription factor activity
- protein binding
- transcription factor binding
Cellular Component
- nucleus
- cytoplasm
- cytosol
- protein-containing complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000234091
- Coding exons
- 2
- Length
- 5609
- Individuals with no LoFs
- 125733
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125735
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0175 | 73 | 73.4 | 0.994 | 0.00000326 | 892 |
| Missense (PolyPhen) | 15 | 22.843 | 0.65666 | 297 | ||
| Synonymous | -4.12 | 63 | 32.9 | 1.91 | 0.00000156 | 263 |
| Loss of Function | 1.76 | 0 | 3.60 | 0.00 | 1.53e-7 | 49 |
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 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcriptional regulator (lacking a basic DNA binding domain) which negatively regulates the basic helix-loop-helix (bHLH) transcription factors by forming heterodimers and inhibiting their DNA binding and transcriptional activity. Implicated in regulating a variety of cellular processes, including cellular growth, senescence, differentiation, apoptosis, angiogenesis, and neoplastic transformation. Inhibits skeletal muscle and cardiac myocyte differentiation. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-ARNTL/BMAL1 heterodimer. Restricts the CLOCK and ARNTL/BMAL1 localization to the cytoplasm. Plays a role in both the input and output pathways of the circadian clock: in the input component, is involved in modulating the magnitude of photic entrainment and in the output component, contributes to the regulation of a variety of liver clock-controlled genes involved in lipid metabolism. {ECO:0000269|PubMed:20861012}.;
Recessive Scores
- pRec
- 0.493
Intolerance Scores
- RVIS EVS
- -0.19
- RVIS percentile EVS
- 39.68
Essentials
- Essential (CRISPR)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.998
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |