19-33301848-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGC

Position:

• chr19-33301848-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGC

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5 BS2

The NM_004364.5(CEBPA):​c.566_567insGCC​(p.Pro188dup) variant causes a 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 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 2.21

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]

(HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.566_567insGCC	p.Pro188dup	inframe_insertion	1/1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001285829.2	c.209_210insGCC	p.Pro69dup	inframe_insertion	1/1		NP_001272758.1
CEBPA	NM_001287424.2	c.671_672insGCC	p.Pro223dup	inframe_insertion	1/1		NP_001274353.1
CEBPA	NM_001287435.2	c.524_525insGCC	p.Pro174dup	inframe_insertion	1/1		NP_001274364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3	c.566_567insGCC	p.Pro188dup	inframe_insertion	1/1		NM_004364.5	ENSP00000427514	P1
	ENST00000587312.1	n.409_411dup		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0000675 AC: 10 AN: 148060 Hom.: 0 Cov.: 32

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: 1 AN: 32872 Hom.: 0 AF XY: 0.0000507 AC XY: 1 AN XY: 19706

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: 61 AN: 1162684 Hom.: 0 Cov.: 32 AF XY: 0.0000598 AC XY: 34 AN XY: 568578

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: 10 AN: 148162 Hom.: 0 Cov.: 32 AF XY: 0.0000692 AC XY: 5 AN XY: 72212

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:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Acute myeloid leukemia Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostics Laboratory, National Institute of Medical Genomics	-	The variant was detected in bone marrow from patients, but it was not confirmed in the matched -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 30, 2023	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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2023

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs746430067; hg19: chr19-33792754;