chr19-33301825-GGCGGGT-G

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.584_589delACCCGC(p.His195_Pro196del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,263,420 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H195H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

CEBPA
NM_004364.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 3.20

Publications

22 publications found

Variant links:

COSMIC-nc: COSV104411195

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 GnomAd4 at 25 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.584_589delACCCGC	p.His195_Pro196del	disruptive_inframe_deletion	Exon 1 of 1	NP_004355.2
CEBPA	NM_001287424.2		c.689_694delACCCGC	p.His230_Pro231del	disruptive_inframe_deletion	Exon 1 of 1	NP_001274353.1
CEBPA	NM_001287435.2		c.542_547delACCCGC	p.His181_Pro182del	disruptive_inframe_deletion	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.584_589delACCCGC	p.His195_Pro196del	disruptive_inframe_deletion	Exon 1 of 1	ENSP00000427514.1
ENSG00000267727	ENST00000587312.1	TSL:3	n.383_388delGGTGCG		non_coding_transcript_exon	Exon 2 of 2
CEBPA-DT	ENST00000718467.1		n.46+42_46+47delGGTGCG		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000169

AC:

AN:

148158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000669

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.000109

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000195

Gnomad OTH

AF:

0.000491

GnomAD2 exomes

AF:

0.000196

AC:

AN:

10180

AF XY:

0.000309

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000760

Gnomad NFE exome

AF:

0.000256

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000291

AC:

324

AN:

1115154

Hom.:

AF XY:

0.000292

AC XY:

158

AN XY:

541312

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

21998

American (AMR)

AF:

0.000113

AC:

AN:

8816

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13896

East Asian (EAS)

AF:

0.00

AC:

AN:

23680

South Asian (SAS)

AF:

0.000548

AC:

AN:

36528

European-Finnish (FIN)

AF:

0.000251

AC:

AN:

23926

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2876

European-Non Finnish (NFE)

AF:

0.000302

AC:

284

AN:

939774

Other (OTH)

AF:

0.0000916

AC:

AN:

43660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000169

AC:

AN:

148266

Hom.:

Cov.:

AF XY:

0.000152

AC XY:

AN XY:

72288

show subpopulations

African (AFR)

AF:

0.000146

AC:

AN:

41082

American (AMR)

AF:

0.0000668

AC:

AN:

14976

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3404

East Asian (EAS)

AF:

0.00

AC:

AN:

4978

South Asian (SAS)

AF:

0.000624

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.000109

AC:

AN:

9208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000195

AC:

AN:

66552

Other (OTH)

AF:

0.000485

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

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.:

Bravo

AF:

0.000181

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 16, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-frame deletion of two amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 34587721, 21455213)

not specified

Uncertain:1

Jul 14, 2022

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

DNA sequence analysis of the CEBPA demonstrated a six base pair deletion in exon 1, c.584_589del. This in-frame deletion is predicted to result in the deletion of two amino acid residues, p.His195_Pro196del. This deletion does not appear to have been previously described in individuals with CEBPA -related disorders. This deletion has not been described in population databases such as ExAC and gnomAD; however the allele frequency estimates may not be reliable in gnomAD (dbSNP rs1002805239). The functional significance of this sequence change is not known at present and its contribution to this individual's disease phenotype cannot definitively be determined.

Inborn genetic diseases

Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.584_589delACCCGC variant (also known as p.H195_P196del) is located in coding exon 1 of the CEBPA gene. This variant results from an in-frame ACCCGC deletion at nucleotide positions 584 to 589. This results in the in-frame deletion of histidine and proline residues at codons 195-196. This amino acid region is not 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.

CEBPA-related disorder

Uncertain:1

Aug 04, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CEBPA c.584_589del6 variant is predicted to result in an in-frame deletion (p.His195_Pro196del). This variant has been reported as a germline variant in an individual with acute myeloid leukemia (Szankasi. 2010. PubMed ID: 20970189). This variant is reported in 0.034% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-33792731-GGCGGGT-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Hereditary cancer-predisposing syndrome

Uncertain:1

Sep 15, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

Acute myeloid leukemia

Uncertain:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.584_589del, results in the deletion of 2 amino acid(s) of the CEBPA protein (p.His195_Pro196del), 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 been observed in individual(s) with acute myeloid leukemia (PMID: 20970189). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

3.2

Mutation Taster

=149/51

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