Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_004364.2 | Alternative | 2385 nt | 1–1077 |
| NM_004364.4 | RefSeq Select | 2631 nt | 151–1227 |
| NM_004364.3 | Alternative | 2591 nt | 111–1187 |
| NM_004364.5 | MANE Select | 2601 nt | 121–1197 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Likely benign (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -333 bp |
| Donor Loss (DL) | 0.0 | 88 bp |
| Acceptor Gain (AG) | 0.0 | 15 bp |
| Donor Gain (DG) | 0.0 | -377 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: it is a missense change (c.562C>T; P188S), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant is not predicted to produce a null effect.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change". The evidence for this variant shows: no previously established pathogenic P188S change is reported. Therefore, this criterion is not applied at Not Applied strength because there is no known pathogenic variant with the same amino acid change.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no de novo status or family segregation data are available. Therefore, this criterion is not applied at Not Applied strength because de novo occurrence has not been demonstrated.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional characterization studies of P188S have been reported. Therefore, this criterion is not applied at Not Applied strength because functional data are lacking.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or disease prevalence data. Therefore, this criterion is not applied at Not Applied strength because there is no evidence of enrichment in affected individuals.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: no information placing P188 in a known hotspot or critical domain. Therefore, this criterion is not applied at Not Applied strength because the variant is not located in a characterized hotspot or domain.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: it is not found in population databases including gnomAD (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from large control datasets.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no evidence of trans occurrence with a pathogenic allele. Therefore, this criterion is not applied at Not Applied strength because there is no trans-phase data.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is a missense substitution without alteration of protein length. Therefore, this criterion is not applied at Not Applied strength because there is no protein length change.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no other pathogenic missense alterations at residue P188 are reported. Therefore, this criterion is not applied at Not Applied strength because there is no known pathogenic variant at the same residue.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo assumption data are available. Therefore, this criterion is not applied at Not Applied strength because assumed de novo status is unsupported.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied at Not Applied strength because familial segregation has not been assessed.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: CEBPA has both loss-of-function and missense disease mechanisms and benign missense variation rates are not especially low. Therefore, this criterion is not applied at Not Applied strength because gene-specific missense prevalence criteria are not met.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: REVEL score 0.05, CADD 2.86, SpliceAI scores 0—all indicating no deleterious impact. Therefore, this criterion is not applied at Not Applied strength because computational predictions do not support deleterious effect.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no phenotype or family history data were provided. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity is not demonstrated.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: no reputable source reports it as pathogenic. Therefore, this criterion is not applied at Not Applied strength because no such report exists.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder". The evidence for this variant shows: absent from population databases (MAF=0%), not exceeding BA1 thresholds. Therefore, this criterion is not applied at Not Applied strength because allele frequency is not high.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder". The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied at Not Applied strength because allele frequency does not exceed expected.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy adult individuals for a dominant (with full penetrance expected at an early age), X-linked or mitochondrial disorder with full penetrance expected at an early age". The evidence for this variant shows: no healthy adult observations with confirmed status. Therefore, this criterion is not applied at Not Applied strength because no such observations exist.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies performed. Therefore, this criterion is not applied at Not Applied strength because functional data are absent.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation analysis is unavailable.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: CEBPA disease mechanism includes both missense and LoF variants. Therefore, this criterion is not applied at Not Applied strength because missense variants can be pathogenic in this gene.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no data on cis/trans phasing with pathogenic variants. Therefore, this criterion is not applied at Not Applied strength because phasing information is absent.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: this is a missense change, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength because the variant type does not match.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: REVEL score 0.05 (<0.15), CADD score 2.86 (low), SpliceAI scores 0. Therefore, this criterion is applied at Supporting strength because computational tools consistently predict no deleterious effect.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no cases with alternative molecular diagnoses. Therefore, this criterion is not applied at Not Applied strength because such case context is lacking.
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: one ClinVar submission classifies it as Likely benign without accessible primary data. Therefore, this criterion is applied at Supporting strength because a reputable clinical database lists it as likely benign without supporting evidence.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is a missense variant, not synonymous. Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.