CBFB
protein-codingcore-binding factor subunit beta
Gene summary
The protein encoded by this gene is the beta subunit of a heterodimeric core-binding transcription factor belonging to the PEBP2/CBF transcription factor family which master-regulates a host of genes specific to hematopoiesis (e.g., RUNX1) and osteogenesis (e.g., RUNX2). The beta subunit is a non-DNA binding regulatory subunit; it allosterically enhances DNA binding by alpha subunit as the complex binds to the core site of various enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers and GM-CSF promoters. Alternative splicing generates two mRNA variants, each encoding a distinct carboxyl terminus. In some cases, a pericentric inversion of chromosome 16 [inv(16)(p13q22)] produces a chimeric transcript consisting of the N terminus of core-binding factor beta in a fusion with the C-terminal portion of the smooth muscle myosin heavy chain 11. This chromosomal rearrangement is associated with acute myeloid leukemia of the M4Eo subtype. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~72.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0859307
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0859307
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0859307
Submitter: Ambry Genetics
Inheritance Pattern: Unknown
Disease ID:MONDO:0018874
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0859307
Submitter: ClinGen
*CBFB* was first reported in relation to autosomal dominant CBFB-related cleidocranial dysplasia in 2022 (Beyltjens et al., PMID: 36241386). This condition has features of clavicular anomalies (varying from unilateral ‘clavicle bipartita’ to bilateral clavicular aplasia); dental anomalies (including delayed or lack of deciduous teeth eruption and supernumerary teeth); skull abnormalities (such as maxillary hypoplasia); and additional bone anomalies (including delayed bone age and pseudoepiphyses of the metacarpals/metatarsals). Six variants (nonsense, frameshift, splicing, large deletion, and complex rearrangement) that have been reported in at least six probands in two publications (PMIDs: 36241386, 39894570) are included in this curation. The mechanism of pathogenicity is reported to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse models, biochemical functional evidence; PMIDs: 12434152, 12434156, 25262822). Mouse models show that mutants have delayed bone formation; lack of clavicles; poor bone calcification; cranial defects; and severely inhibited osteoblast differentiation and chondrocyte maturation. Biochemical functional evidence shows that the gene is key in RUNX protein family stability and osteoblast/chondrocyte differentiation. In summary, there is definitive evidence supporting the relationship between *CBFB* and autosomal dominant CBFB-related cleidocranial dysplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date 2/19/2026 (SOP Version 12).
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CBFB variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_022845.3. 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 | 3 | 1 | 4 | |||
| missense | 1 | 6 | 1 | 8 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 3 | 3 | ||||
| splice donor/acceptor (+/-2bp) | 2 | 7 | 9 | |||
| Total | 2 | 1 | 20 | 2 | 0 | 25 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_074036.1 | 6 | MANE Select | |
| Ensembl | ENSP00000415151.2 | 6 | MANE Select | |
| RefSeq | NP_001355636.1 | 5 | Standard | |
| RefSeq | NP_001355637.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cbfb | Danio rerio | Structure: cardiac muscle cell Quality: has fewer parts of type abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- miR-targeted genes in lymphocytes - TarBase
- miR-targeted genes in muscle cell - TarBase
- miR-targeted genes in squamous cell - TarBase
- Dual hijack model of Vif in HIV infection
- RUNX2 regulates osteoblast differentiation
Biological Process
- negative regulation of transcription by RNA polymerase II
- protein polyubiquitination
- osteoblast differentiation
- regulation of cytokine-mediated signaling pathway
- transcription by RNA polymerase II
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA binding
- DNA-binding transcription factor activity
- transcription coregulator activity
- transcription coactivator activity
Cellular Component
- nucleus
- nucleoplasm
- membrane
- core-binding factor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000412916
- Coding exons
- 6
- Length
- 71943
- Individuals with no LoFs
- 125743
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125745
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.71 | 58 | 108 | 0.536 | 0.00000566 | 1222 |
| Missense (PolyPhen) | 12 | 38.033 | 0.31552 | 396 | ||
| Synonymous | -0.942 | 45 | 37.6 | 1.20 | 0.00000182 | 330 |
| Loss of Function | 3.27 | 1 | 14.4 | 0.0695 | 8.75e-7 | 136 |
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 | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Forms the heterodimeric complex core-binding factor (CBF) with RUNX family proteins (RUNX1, RUNX2, and RUNX3). RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'-TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA- binding capacity of RUNX. The heterodimers bind to the core site of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters. CBF complexes repress ZBTB7B transcription factor during cytotoxic (CD8+) T cell development. They bind to RUNX-binding sequence within the ZBTB7B locus acting as transcriptional silencer and allowing for cytotoxic T cell differentiation. {ECO:0000250|UniProtKB:Q08024}.;
- Disease
- DISEASE: Note=A chromosomal aberration involving CBFB is associated with acute myeloid leukemia of M4EO subtype. Pericentric inversion inv(16)(p13;q22). The inversion produces a fusion protein that consists of the 165 N-terminal residues of CBF-beta (PEPB2) with the tail region of MYH11. {ECO:0000269|PubMed:8351518}.;
Recessive Scores
- pRec
- 0.220
Intolerance Scores
- LoFtool
- 0.158
- RVIS EVS
- -0.01
- RVIS percentile EVS
- 52.85
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.557
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |