19-33302163-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_004364.5(CEBPA):c.252C>G(p.His84Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000183 in 1,472,820 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. H84L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CEBPA
NM_004364.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 4.25

Publications

2 publications found

Variant links:

COSMIC-nc: COSV105881783

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:

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

CEBPA-DT links:

ENSG00000267727 (HGNC:):

ENSG00000267727 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.41409647).

BP6

Variant 19-33302163-G-C is Benign according to our data. Variant chr19-33302163-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239920. Variant chr19-33302163-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239920. Variant chr19-33302163-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239920. Variant chr19-33302163-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239920.

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5 link	c.252C>G	p.His84Gln	missense_variant	Exon 1 of 1	ENST00000498907.3	NP_004355.2	P49715-1
CEBPA	NM_001287424.2 link	c.357C>G	p.His119Gln	missense_variant	Exon 1 of 1		NP_001274353.1	P49715-4
CEBPA	NM_001287435.2 link	c.210C>G	p.His70Gln	missense_variant	Exon 1 of 1		NP_001274364.1	P49715-2
CEBPA	NM_001285829.2 link	c.-106C>G		5_prime_UTR_variant	Exon 1 of 1		NP_001272758.1	P49715-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CEBPA	ENST00000498907.3 link	c.252C>G	p.His84Gln	missense_variant	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1	P49715-1
CEBPA-DT	ENST00000718467.1 link	n.46+364G>C		intron_variant	Intron 1 of 1
ENSG00000267727	ENST00000587312.1 link	n.*223G>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151382

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000174

AC:

AN:

1321438

Hom.:

Cov.:

AF XY:

0.0000199

AC XY:

AN XY:

651674

show subpopulations

African (AFR)

AF:

0.0000747

AC:

AN:

26778

American (AMR)

AF:

0.00

AC:

AN:

27402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22802

East Asian (EAS)

AF:

0.00

AC:

AN:

28244

South Asian (SAS)

AF:

0.00

AC:

AN:

71286

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46574

Middle Eastern (MID)

AF:

0.000372

AC:

AN:

5370

European-Non Finnish (NFE)

AF:

0.0000173

AC:

AN:

1039078

Other (OTH)

AF:

0.0000186

AC:

AN:

53904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.0000264

AC:

AN:

151382

Hom.:

Cov.:

AF XY:

0.0000406

AC XY:

AN XY:

73906

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41342

American (AMR)

AF:

0.00

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5082

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67800

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Acute myeloid leukemia

Uncertain:3

Aug 07, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 84 of the CEBPA protein (p.His84Gln). 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: 239920). 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. -

Mar 30, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 15, 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

Uncertain

0.55

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.68

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.5

PhyloP100

4.2

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-2.1

REVEL

Benign

0.091

Sift

Uncertain

0.0050

Sift4G

Benign

0.23

Polyphen

0.97

Vest4

0.31

MutPred

0.23

Gain of solvent accessibility (P = 0.0374);

MVP

0.39

ClinPred

0.95

GERP RS

4.1

PromoterAI

0.019

Neutral

(source)

Varity_R

0.20

gMVP

0.44

Mutation Taster

=59/41

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