19-33301825-GGCGGGTGCGGGT-GGCGGGTGCGGGTGCGGGTGCGGGT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_004364.5(CEBPA):c.578_589dupACCCGCACCCGC(p.His193_Pro196dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000712 in 1,263,760 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P197P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000054 ( 0 hom. )

Consequence

CEBPA
NM_004364.5 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.645

Publications

22 publications found

Variant links:

Genes affected

CEBPA (HGNC:1833): (CCAAT enhancer binding protein alpha) This intronless gene encodes a transcription factor that contains a basic leucine zipper (bZIP) domain and recognizes the CCAAT motif in the promoters of target genes. The encoded protein functions in homodimers and also heterodimers with CCAAT/enhancer-binding proteins beta and gamma. Activity of this protein can modulate the expression of genes involved in cell cycle regulation as well as in body weight homeostasis. Mutation of this gene is associated with acute myeloid leukemia. The use of alternative in-frame non-AUG (GUG) and AUG start codons results in protein isoforms with different lengths. Differential translation initiation is mediated by an out-of-frame, upstream open reading frame which is located between the GUG and the first AUG start codons. [provided by RefSeq, Dec 2013]

CEBPA links:

ENSG00000267727 (HGNC:):

ENSG00000267727 links:

CEBPA-DT (HGNC:25710): (CEBPA divergent transcript)

CEBPA-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004364.5

BS2

High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004364.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEBPA	NM_004364.5	MANE Select	c.578_589dupACCCGCACCCGC	p.His193_Pro196dup	conservative_inframe_insertion	Exon 1 of 1	NP_004355.2
CEBPA	NM_001287424.2		c.683_694dupACCCGCACCCGC	p.His228_Pro231dup	conservative_inframe_insertion	Exon 1 of 1	NP_001274353.1
CEBPA	NM_001287435.2		c.536_547dupACCCGCACCCGC	p.His179_Pro182dup	conservative_inframe_insertion	Exon 1 of 1	NP_001274364.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEBPA	ENST00000498907.3	TSL:6 MANE Select	c.578_589dupACCCGCACCCGC	p.His193_Pro196dup	conservative_inframe_insertion	Exon 1 of 1	ENSP00000427514.1
ENSG00000267727	ENST00000587312.1	TSL:3	n.377_388dupGGTGCGGGTGCG		non_coding_transcript_exon	Exon 2 of 2
CEBPA-DT	ENST00000718467.1		n.46+36_46+47dupGGTGCGGGTGCG		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000202

AC:

AN:

148158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000400

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000538

AC:

AN:

1115494

Hom.:

Cov.:

AF XY:

0.00000739

AC XY:

AN XY:

541526

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21998

American (AMR)

AF:

0.00

AC:

AN:

8828

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13910

East Asian (EAS)

AF:

0.000169

AC:

AN:

23690

South Asian (SAS)

AF:

0.0000273

AC:

AN:

36604

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2876

European-Non Finnish (NFE)

AF:

0.00000106

AC:

AN:

939972

Other (OTH)

AF:

0.00

AC:

AN:

43670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000202

AC:

AN:

148266

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41082

American (AMR)

AF:

0.00

AC:

AN:

14976

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3404

East Asian (EAS)

AF:

0.000402

AC:

AN:

4978

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66552

Other (OTH)

AF:

0.00

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

May 06, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.578_589dup12 variant (also known as p.H193_P196dup), located in coding exon 1 of the CEBPA gene, results from an in-frame duplication of 12 nucleotides at nucleotide positions 578 to 589. This results in the duplication of 4 extra residues (HPHP) between codons 193 and 196. This amino acid region is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear.

Hereditary cancer-predisposing syndrome

Uncertain:1

Sep 16, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

Acute myeloid leukemia

Uncertain:1

Sep 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.578_589dup, results in the insertion of 4 amino acid(s) of the CEBPA protein (p.His193_Pro196dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CEBPA-related conditions. ClinVar contains an entry for this variant (Variation ID: 408758). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.65

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over