CEBPA

Gene Facts

• HGNC Symbol: CEBPA (HGNC:1833)
• HGNC Name: CCAAT enhancer binding protein alpha
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: CEBP
• Alias symbols: C/EBP-alpha
• %HI: 47.24
• pLI: 0.26
• LOEUF: 1.37
• Cytoband: 19q13.11
• Genomic Coordinates:

  GRCh37/hg19:	chr19:33790840-33793470
  GRCh38/hg38:	chr19:33299934-33302534

• MANE Select Transcript: NM_004364.5 ENST00000498907.3
• Function: Transcription factor that coordinates proliferation arrest and the differentiation of myeloid progenitors, adipocytes, hepatocytes, and cells of the lung and the placenta. Binds directly to the consensus DNA sequence 5'-T[TG]NNGNAA[TG]-3' acting as an activator on distinct target genes (PubMed:11242107). During early embryogenesis, plays essential and redundant functions with CEBPB. Essential for the transition from common myeloid progenitors (CMP) to granulocyte/monocyte progenitors (GMP). Crit... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-22352
• ClinGen Curation ID: CCID:006833
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: No Evidence for Haploinsufficiency (0)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 06/09/2022

Haploinsufficiency (HI) Score Details

• HI Score: 0
• HI Evidence Strength: No Evidence for Haploinsufficiency

HI Disease

• acute myeloid leukemia

• HI Evidence Comments: While both truncating and in-frame deletion mutations were reported in CEBPa gene, in vitro studies demonstrate a dominant negative effect of these mutants (PMID: 11242107 and19706798). Currently, there is no report of AML caused by the deletion of entire CEBPa gene. 11242107, 19706798 Pabst et al. (2001) carried out an in vitro protein expression study. It was found that in addition to the 20-KD truncated protein generated by mutants with stop codon at position 159 (P39fsX159, G36fsX159, F82fsX159), all samples carrying N-terminal mutations also have a 30-KD protein produced from an alternative intragenic initiation codon at position 120 (the wild type protein is 42-KD). The mutant 30-KD protein demonstrates a dominant negative effect (reduce the DNA-binding capacity of the wild type protein). The C-terminal mutants located in the basic zipper domain of the protein and often are in-frame insertions or deletions, also demonstrated an reduced DNA binding capacity. 21177436 Taskesen et al. (2010) reported the CEBPA mutation status in 1,182 cytogenetically normal AML patients. Germline mutation was found in 7% (5 /71) of the CEBPA mutation positive patients. Mutations are found in both N-terminal and C-terminal of the protein. Two of the germline mutations are predicted to yield an truncated protein (338delC, 307delG). Somatic mutations were identified in four of the five patients. 26162409 Tawana et al. (2015) carried out germline WES and NGS genetic profiling of tumors in 10 CEBPA-mutated families (9 families that were previously reported). It was found that germline mutations tend to be clustered within the N-terminal. The mutations are highly penetrant. AML was diagnosed at a median age of 24.5 years old (1.75 -46 years). In all diagnostic tumors, double mutations were detected and somatic mutations were unstable throughout the disease course. A new pedigree was found to harbor c.218insC (p.His24Alafx*84) germline mutation. Other previously reported germline truncating mutations include 338delC, 307delG (PMID:21177436), 212delC (PMID:15575056), 217incC (PMID:15902292), 291delC, 465insT, 217insC, 250insCTAC (PMID: 18758433) etc. 35032366 Wafa et al. (2022) reported a family of four with AML (father, three affected children), a germline mutation c.198deupC (p.Tyr67Leufs*41) was detected in this family. The age of onset of AML in the father is 37 years and 2.5 - 8 years in the children. 15575056 Smith et al. (2004) reported a family of three members with acute myeloid leukemia (AML). The father was diagnosed with AML (FAB subtype M1) at the age of 10 and in lasting remission stage, no karyotype and other genetic testing was documented at the time of diagnosis and treatment. The son was diagnosed with AML (M2Eo) at the age of 30, with normal karyotype and negative for t(8;21) by FISH. The daughter was diagnosed with AML at the age of 18 (M2Eo) with normal cytogenetics. Germline heterozygous mutation 212delC (predicted to yield a termination codon at 158) was detected in all three individuals. A somatic allele (in trans with the germline mutation) was also detected in the son. No mutations were identified in the exons of KRAS, NRAS, KIT, PTPN11, FES, FLT3 and RUNX1.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: There is no evidence of triplosensitivity at this time.