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CEBPAc.926_928dupLikely pathogenic
Print report
Variant interpretation report

CEBPA c.926_928dup, p.(Glu309_Thr310insLys)

NM_004364.3:c.926_928dup NP_004355.2:p.(Glu309_Thr310insLys) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About CEBPA

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Moderate
PM1 · moderate

The variant is located at codon 309-310 within the CEBPA bZIP domain (approximately codons 278-358), a well-established critical functional domain required for DNA binding and dimerization. Pathogenic CEBPA mutations cluster in the bZIP domain, and no benign variants are reported in this region.

PM2Moderate
PM2 · moderate

The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency = 0.0), meeting the <0.1% threshold for PM2 in the absence of a gene-specific CSPEC framework.

PM4Moderate
PM4 · moderate

The variant is an in-frame duplication (c.926_928dup) resulting in insertion of a lysine residue (p.Glu309_Thr310insLys), causing protein length change in a non-repeat region. This meets the PM4 criterion for in-frame insertions in a non-repeat region.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate, PM4 moderate; combination = 3 moderate, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
9 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV57195593, n = 9 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 10 not met · 9 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PM1 (moderate): The variant lies within the CEBPA bZIP domain (codons ~278-358), a well-established critical functional domain where pathogenic mutations cluster. No benign variation is observed in this region.

PM2 (moderate): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0.0), meeting the <0.1% threshold for moderate evidence of rarity.

PM4 (moderate): The variant is an in-frame duplication (p.Glu309_Thr310insLys) causing protein length change in a non-repeat region, consistent with a disease-causing mechanism.

Three moderate criteria (PM1, PM2, PM4) are met with no benign criteria met. Per ACMG/AMP 2015 combination rules (PMID:25741868), ≥3 moderate criteria support classification as Likely Pathogenic.

Met · 3

PM1 ModerateThe variant is located at codon 309-310 within the CEBPA bZIP domain (approximately codons 278-358), a well-established critical functional domain required for DNA binding and dimerization. Pathogenic CEBPA mutations cluster in the bZIP domain, and no benign variants are reported in this region. Details ▾Hide ▴
Evidence considered
  • Variant lies within the bZIP domain (codons ~278-358)
  • a critical functional domain
  • absent from gnomAD suggesting no benign variation in this region.
Still missing
  • No CSPEC-defined PM1 domain boundaries for CEBPA
  • domain assignment based on literature.
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM2 ModerateThe variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency = 0.0), meeting the <0.1% threshold for PM2 in the absence of a gene-specific CSPEC framework. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (AF=0)
  • gnomAD v4.1 (AF=0)
  • gnomAD-Canada v1.0 (AF=0.0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PM4 ModerateThe variant is an in-frame duplication (c.926_928dup) resulting in insertion of a lysine residue (p.Glu309_Thr310insLys), causing protein length change in a non-repeat region. This meets the PM4 criterion for in-frame insertions in a non-repeat region. Details ▾Hide ▴
Evidence considered
  • In-frame duplication causing p.Glu309_Thr310insLys
  • protein length change in a non-repeat region.

Not met · 10 · evaluated, threshold not reached

PP3 Multiple lines of computational evidence supporting pathogenicity are not available. REVEL and BayesDel are not applicable to indels. SpliceAI predicts no splice impact (max delta score = 0.01). No HCI prior probability score is available for CEBPA. Insufficient computational evidence to support PP3. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.01 (no splice impact)
  • REVEL/BayesDel unavailable for indels
  • HCI prior not found for CEBPA.
Still missing
  • No in silico tools specifically calibrated for in-frame indel pathogenicity prediction available.
Sources
spliceai ↗
PP5 No germline clinical diagnostic laboratory or expert panel has classified this variant as pathogenic or likely pathogenic. OncoKB's 'Likely Oncogenic' designation is a somatic cancer biomarker annotation and does not constitute a germline variant classification suitable for PP5. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • OncoKB somatic classification (Likely Oncogenic) is not a germline pathogenicity assertion.
Sources
oncokb ↗clinvar ↗
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0.0). Does not meet the >1% population frequency threshold for BA1. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations (AF=0.0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0.0). Does not meet the >0.3% population frequency threshold for BS1. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations (AF=0.0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 The variant is absent from population databases; no observation in healthy adults, either homozygously or in trans with a known pathogenic variant, has been reported. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • no observation in any control population.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP2 The variant has not been observed in trans with a known pathogenic variant in any database or publication. Details ▾Hide ▴
Evidence considered
  • Not observed in trans with any pathogenic CEBPA variant.
Sources
gnomad_v2 ↗gnomad_v4 ↗clinvar ↗
BP3 BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This variant is in the bZIP domain, a region with well-established critical function for DNA binding and dimerization, and is not in a repetitive region. Details ▾Hide ▴
Evidence considered
  • Variant is in the bZIP domain
  • a region with well-established function
  • not in a repetitive region.
BP4 Multiple lines of computational evidence suggesting no impact are not available. SpliceAI predicts no splice effect (max delta = 0.01), but REVEL and BayesDel are not applicable to indels. A single line of splice evidence is insufficient to meet BP4, and the variant's location in the bZIP functional domain does not support a benign computational prediction. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.01 (no splice impact)
  • REVEL/BayesDel unavailable for indels
  • insufficient for multiple lines of benign computational evidence.
Still missing
  • No in silico tools calibrated for in-frame indel benign prediction.
Sources
spliceai ↗
BP5 The variant has not been observed in any case with an alternate molecular basis for disease. No such data are available. Details ▾Hide ▴
Evidence considered
  • No observation in a case with alternate molecular explanation.
BP6 No reputable source has classified this variant as benign or likely benign. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no benign classification from any source.
Sources
clinvar ↗

Not assessed · 9 · no assessment recorded

PS2 No de novo observation data are available for this variant in any database or publication reviewed. Details ▾Hide ▴
Still missing
  • No de novo testing or reporting data available.
PS3 No variant-specific functional studies were identified. Five publications (PMID:11830484, 33951732, 34320176, 34448807, 38228680) discuss CEBPA mutations at the gene level in AML prognosis but do not report functional characterization of NM_004364.3:c.926_928dupAGA. Full-text search of available papers confirmed the variant is not mentioned. Details ▾Hide ▴
Evidence considered
  • Five CEBPA-focused publications reviewed
  • none contain variant-specific functional data for c.926_928dupAGA.
Still missing
  • No functional studies (e.g.
  • luciferase reporter
  • DNA-binding assay
  • expression analysis) performed on this specific variant.
PS4 The variant is absent from ClinVar and absent from gnomAD; no case-control data are available to evaluate whether prevalence is significantly increased in affected individuals versus controls. COSMIC somatic occurrence (COSV57195593, n=9) does not inform germline PS4. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • absent from gnomAD v2.1 and v4.1
  • observed somatically in COSMIC (n=9).
Still missing
  • No case-control studies or clinical cohort data for this variant.
Sources
gnomad_v2 ↗gnomad_v4 ↗clinvar ↗
PM6 No de novo observation data are available for this variant. PM6 requires confirmed de novo occurrence with parental testing. Details ▾Hide ▴
Still missing
  • No de novo testing or reporting data available.
PP1 No cosegregation data are available for this variant in any family. Details ▾Hide ▴
Still missing
  • No family studies or cosegregation data available.
PP4 No patient-specific phenotype or family history data are available for this variant. PP4 requires the patient's phenotype or family history to be highly specific for the disease. Details ▾Hide ▴
Still missing
  • No clinical phenotype data available for assessment.
BS3 No variant-specific functional studies demonstrating no deleterious effect have been identified. The five publications reviewed (PMID:11830484, 33951732, 34320176, 34448807, 38228680) discuss CEBPA mutations at the gene level but do not report functional data for c.926_928dupAGA. Full-text search of available papers confirmed the variant is not mentioned. Details ▾Hide ▴
Evidence considered
  • Five CEBPA-focused publications reviewed
  • none contain variant-specific functional data for c.926_928dupAGA.
Still missing
  • No functional studies available to evaluate the effect of this specific in-frame insertion.
BS4 No cosegregation data are available to assess whether the variant fails to segregate with disease in affected families. Details ▾Hide ▴
Still missing
  • No family studies available.
PS5 No reputable germline diagnostic source has reported this variant as pathogenic with supporting evidence suitable for PS5. OncoKB classifies this variant as 'Likely Oncogenic' in a somatic context, which does not constitute a germline pathogenicity assertion. Details ▾Hide ▴
Evidence considered
  • OncoKB somatic classification: Likely Oncogenic (not a germline assertion).
Still missing
  • No germline clinical laboratory or expert panel classification available.
Sources
oncokb ↗
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_004364.3:c.926_928dup is an in-frame duplication (p.Glu309_Thr310insLys), not a null variant (nonsense, frameshift, or canonical splice). Per ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 does not apply to in-frame insertions. Details ▾Hide ▴
Evidence considered
  • In-frame duplication
  • variant bucket 'other' per PVS1 variant assessment
  • does not meet null-variant criteria.
Sources
pvs1_generic_framework ↗
PS1 N/APS1 requires a different nucleotide change leading to the same amino acid change that has been previously classified as pathogenic. No such comparator pathogenic variant exists for p.Glu309_Thr310insLys. Details ▾Hide ▴
Evidence considered
  • No known pathogenic variant at this residue with the same amino acid consequence from a different nucleotide change.
PM3 N/APM3 (observed in trans with a pathogenic variant) was not assessed per user direction — skipped as trivially not applicable. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to missense variants at a residue where a different missense change has been classified as pathogenic. This variant is an in-frame insertion (p.Glu309_Thr310insLys), not a missense change. The automated PM5 candidate search confirmed this is not applicable. Details ▾Hide ▴
Evidence considered
  • In-frame insertion
  • not a missense variant
  • no same-residue pathogenic missense comparator applicable.
Sources
pm5_candidates
PP2 N/APP2 applies specifically to missense variants in genes with a low rate of benign missense variation. This variant is an in-frame duplication, not a missense variant. Details ▾Hide ▴
Evidence considered
  • In-frame duplication
  • PP2 is restricted to missense variants per ACMG/AMP guidelines.
BP1 N/ABP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. This variant is an in-frame duplication, not a missense variant. Details ▾Hide ▴
Evidence considered
  • In-frame duplication
  • BP1 is restricted to missense variants per ACMG/AMP guidelines.
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This variant is an in-frame duplication, not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • NM_004364.3:c.926_928dupAGA is an in-frame duplication
  • not a synonymous variant.

Identifiers

Gene
CEBPA
Transcript
NM_004364.3
Coding (HGVS c.)
NM_004364.3:c.926_928dup
Protein (HGVS p.)
NP_004355.2:p.(Glu309_Thr310insLys)
GRCh38
chr19:33301486 G>GTCT
GRCh37
chr19:33792392 G>GTCT
COSMIC
COSV57195593

Gene diagram

Every interpreted variant in CEBPA, mapped onto the exon structure of NM_004364.3. Select a row to find it on the plot.

CEBPANM_004364.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +307 bp
0.000
SpliceAI acceptor gainat +100 bp
0.000
SpliceAI donor lossat -144 bp
0.000
SpliceAI donor gainat -10 bp
0.010
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.020

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 Multiple lines of computational evidence supporting pathogenicity are not available. REVEL and BayesDel are not applicable to indels. SpliceAI predicts no splice impact (max delta score = 0.01). No HCI prior probability score is available for CEBPA. Insufficient computational evidence to support PP3. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.01 (no splice impact)
  • REVEL/BayesDel unavailable for indels
  • HCI prior not found for CEBPA.
Still missing
  • No in silico tools specifically calibrated for in-frame indel pathogenicity prediction available.
Sources
spliceai ↗
BP4 Multiple lines of computational evidence suggesting no impact are not available. SpliceAI predicts no splice effect (max delta = 0.01), but REVEL and BayesDel are not applicable to indels. A single line of splice evidence is insufficient to meet BP4, and the variant's location in the bZIP functional domain does not support a benign computational prediction. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.01 (no splice impact)
  • REVEL/BayesDel unavailable for indels
  • insufficient for multiple lines of benign computational evidence.
Still missing
  • No in silico tools calibrated for in-frame indel benign prediction.
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This variant is an in-frame duplication, not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • NM_004364.3:c.926_928dupAGA is an in-frame duplication
  • not a synonymous variant.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias.
    Surveyed CEBPA mutations in 408 patient samples and 5 cell lines across 11 cancer types including MDS and AML. NM_004364.3:c.926_928dupAGA was not identified in this paper.
    Does not name this variant
    PMID 11830484 ↗
  • CEBPA-bZip mutations are associated with favorable prognosis in de novo AML: a report from the Children's Oncology Group.
    Evaluated CEBPA-bZip mutation status in 2958 pediatric/young adult AML patients from Children's Oncology Group trials, demonstrating favorable prognosis for bZIP-mutated cases. NM_004364.3:c.926_928dupAGA was searched in the full text and was not identified.
    Does not name this variant
    PMID 33951732 ↗
  • CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome.
    Retrospectively analyzed CEBPA mutations in 4708 adult AML patients, examining differential prognostic impact of bZIP and TAD domain mutations. NM_004364.3:c.926_928dupAGA was not identified in the abstract or available content.
    Does not name this variant
    PMID 34320176 ↗
  • Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia.
    Investigated prognostic impact of CEBPA bZIP domain mutations in 1028 AML patients, finding favorable outcomes in bZIP-mutated cases. NM_004364.3:c.926_928dupAGA was searched in the full text and was not identified.
    Does not name this variant
    PMID 34448807 ↗
  • Prognostic impact of CEBPA mutational subgroups in adult AML.
    Pooled analysis of 1010 CEBPA-mutant adult AML patients comparing mutational subgroups by bZIP mutation type and allelic state. NM_004364.3:c.926_928dupAGA was searched in the full text and was not identified.
    Does not name this variant
    PMID 38228680 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57195593, n = 9 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.