19-33301883-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004364.5(CEBPA):c.532C>G(p.Leu178Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000225 in 1,330,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L178F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 32)

Exomes 𝑓: 8.5e-7 ( 0 hom. )

Consequence

CEBPA
NM_004364.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.00

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2432774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CEBPA	NM_004364.5 link	c.532C>G	p.Leu178Val	missense_variant	Exon 1 of 1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2 link	c.637C>G	p.Leu213Val	missense_variant	Exon 1 of 1		NP_001274353.1
CEBPA	NM_001287435.2 link	c.490C>G	p.Leu164Val	missense_variant	Exon 1 of 1		NP_001274364.1
CEBPA	NM_001285829.2 link	c.175C>G	p.Leu59Val	missense_variant	Exon 1 of 1		NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CEBPA	ENST00000498907.3 link	c.532C>G	p.Leu178Val	missense_variant	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1
ENSG00000267727	ENST00000587312.1 link	n.425G>C		non_coding_transcript_exon_variant	Exon 2 of 2	3
CEBPA-DT	ENST00000718467.1 link	n.46+84G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

148022

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000302

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.46e-7

AC:

AN:

1182624

Hom.:

Cov.:

AF XY:

0.00000172

AC XY:

AN XY:

579792

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23646

American (AMR)

AF:

0.00

AC:

AN:

18194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18316

East Asian (EAS)

AF:

0.00

AC:

AN:

24384

South Asian (SAS)

AF:

0.00

AC:

AN:

51818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28666

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3218

European-Non Finnish (NFE)

AF:

0.00000103

AC:

AN:

967974

Other (OTH)

AF:

0.00

AC:

AN:

46408

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000135

AC:

AN:

148022

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

72056

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41032

American (AMR)

AF:

0.00

AC:

AN:

14952

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3396

East Asian (EAS)

AF:

0.00

AC:

AN:

5068

South Asian (SAS)

AF:

0.00

AC:

AN:

4760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000302

AC:

AN:

66334

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Acute myeloid leukemia

Uncertain:2

Oct 17, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 178 of the CEBPA protein (p.Leu178Val). This variant is not present in population databases (gnomAD no frequency). 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: 526799). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CEBPA protein function with a negative predictive value of 80%. 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.

not specified

Uncertain:1

Nov 25, 2020

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change is absent from the large population databases such as ExAC and gnomAD (dbSNP rs1325138029). The p.Leu178Val change affects a moderately conserved amino acid residue located in a domain of the CEBPA protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Leu178Val substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Leu178Val change remains unknown at this time.

not provided

Uncertain:1

Mar 10, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense 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: 29703253, 21455213, 30089904)

Inborn genetic diseases

Benign:1

Mar 03, 2025

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.71

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

2.0

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.67

REVEL

Benign

0.039

Sift

Uncertain

0.025

Sift4G

Benign

0.097

Vest4

0.23

ClinPred

0.28

GERP RS

3.6

Varity_R

0.24

gMVP

0.28

Mutation Taster

=80/20

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over