19-33301848-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGC

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5BS2

The NM_004364.5(CEBPA):c.564_566dupGCC(p.Pro189dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000542 in 1,310,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

CEBPA
NM_004364.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 2.21

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP5

Variant 19-33301848-G-GGGC is Pathogenic according to our data. Variant chr19-33301848-G-GGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 408742.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5 link	c.564_566dupGCC	p.Pro189dup	disruptive_inframe_insertion	Exon 1 of 1	ENST00000498907.3	NP_004355.2	P49715-1
CEBPA	NM_001287424.2 link	c.669_671dupGCC	p.Pro224dup	disruptive_inframe_insertion	Exon 1 of 1		NP_001274353.1	P49715-4
CEBPA	NM_001287435.2 link	c.522_524dupGCC	p.Pro175dup	disruptive_inframe_insertion	Exon 1 of 1		NP_001274364.1	P49715-2
CEBPA	NM_001285829.2 link	c.207_209dupGCC	p.Pro70dup	disruptive_inframe_insertion	Exon 1 of 1		NP_001272758.1	P49715-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3 link	c.564_566dupGCC	p.Pro189dup	disruptive_inframe_insertion	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1		P49715-1
ENSG00000267727	ENST00000587312.1 link	n.409_411dupGGC		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000675

AC:

AN:

148060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000488

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000753

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000304

AC:

AN:

32872

Hom.:

AF XY:

0.0000507

AC XY:

AN XY:

19706

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 SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000525

AC:

AN:

1162684

Hom.:

Cov.:

AF XY:

0.0000598

AC XY:

AN XY:

568578

show subpopulations

Gnomad4 AFR exome

AF:

0.000130

Gnomad4 AMR exome

AF:

0.0000654

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000292

Gnomad4 SAS exome

AF:

0.000145

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000438

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000675

AC:

AN:

148162

Hom.:

Cov.:

AF XY:

0.0000692

AC XY:

AN XY:

72212

show subpopulations

Gnomad4 AFR

AF:

0.0000487

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000197

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000753

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Acute myeloid leukemia

Pathogenic:1Uncertain:1

Genomic Diagnostics Laboratory, National Institute of Medical Genomics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant was detected in bone marrow from patients, but it was not confirmed in the matched -

Aug 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.564_566dup, results in the insertion of 1 amino acid(s) of the CEBPA protein (p.Pro189dup), 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: 408742). 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. -

not provided

Uncertain:1

Mar 16, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame insertion of 1 amino acid in a non-repeat region; Observed in an individual with pediatric acute myeloid leukemia (Molina Garay et al., 2022); This variant is associated with the following publications: (PMID: 21455213, 35967564) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over