19-33301848-GGGCGGCGGCGGC-GGGCGGCGGC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3BP6

The NM_004364.5(CEBPA):c.564_566delGCC(p.Pro189del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,289,206 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P188P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 0 hom. )

Consequence

CEBPA
NM_004364.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 2.21

Publications

2 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 -2 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004364.5

BP6

Variant 19-33301848-GGGC-G is Benign according to our data. Variant chr19-33301848-GGGC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 641289.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CEBPA	NM_004364.5 link	c.564_566delGCC	p.Pro189del	disruptive_inframe_deletion	Exon 1 of 1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2 link	c.669_671delGCC	p.Pro224del	disruptive_inframe_deletion	Exon 1 of 1		NP_001274353.1
CEBPA	NM_001287435.2 link	c.522_524delGCC	p.Pro175del	disruptive_inframe_deletion	Exon 1 of 1		NP_001274364.1
CEBPA	NM_001285829.2 link	c.207_209delGCC	p.Pro70del	disruptive_inframe_deletion	Exon 1 of 1		NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CEBPA	ENST00000498907.3 link	c.564_566delGCC	p.Pro189del	disruptive_inframe_deletion	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1
ENSG00000267727	ENST00000587312.1 link	n.409_411delGGC		non_coding_transcript_exon_variant	Exon 2 of 2	3
CEBPA-DT	ENST00000718467.1 link	n.46+68_46+70delGGC		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000270

AC:

AN:

148056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000488

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000294

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0107

AC:

353

AN:

32872

AF XY:

0.0105

show subpopulations

Gnomad AFR exome

AF:

0.00448

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.00671

Gnomad EAS exome

AF:

0.00708

Gnomad FIN exome

AF:

0.0110

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.0119

GnomAD4 exome

AF:

0.00203

AC:

2322

AN:

1141150

Hom.:

AF XY:

0.00231

AC XY:

1289

AN XY:

557336

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00150

AC:

AN:

22682

American (AMR)

AF:

0.00846

AC:

124

AN:

14660

Ashkenazi Jewish (ASJ)

AF:

0.00424

AC:

AN:

16502

East Asian (EAS)

AF:

0.00204

AC:

AN:

23508

South Asian (SAS)

AF:

0.00845

AC:

389

AN:

46034

European-Finnish (FIN)

AF:

0.00517

AC:

133

AN:

25716

Middle Eastern (MID)

AF:

0.00359

AC:

AN:

3068

European-Non Finnish (NFE)

AF:

0.00147

AC:

1388

AN:

944134

Other (OTH)

AF:

0.00279

AC:

125

AN:

44846

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.260

Heterozygous variant carriers

323

646

968

1291

1614

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:

0.0000270

AC:

AN:

148056

Hom.:

Cov.:

AF XY:

0.0000416

AC XY:

AN XY:

72096

show subpopulations

African (AFR)

AF:

0.0000488

AC:

AN:

40988

American (AMR)

AF:

0.00

AC:

AN:

14940

Ashkenazi Jewish (ASJ)

AF:

0.000294

AC:

AN:

3398

East Asian (EAS)

AF:

0.00

AC:

AN:

5092

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9160

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000151

AC:

AN:

66408

Other (OTH)

AF:

0.00

AC:

AN:

2040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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.:

Asia WGS

AF:

0.00135

AC:

AN:

2988

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Aug 18, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Acute myeloid leukemia

Uncertain:1

Apr 14, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant has not been reported in the literature in individuals with CEBPA-related disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant, c.564_566delGCC, results in the deletion of 1 amino acid(s) of the CEBPA protein (p.Pro189del), but otherwise preserves the integrity of the reading frame. -

Inborn genetic diseases

Benign:1

Mar 20, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Jul 09, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CEBPA-related disorder

Benign:1

Mar 08, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.2

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over