19-33301848-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCGGC

Variant names:

• chr19-33301848-G-GGGCGGCGGC
• rs746430067
• NM_004364.5:c.558_566dupGCCGCCGCC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_004364.5(CEBPA):​c.558_566dupGCCGCCGCC​(p.Pro187_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 0.00000229 in 1,310,768 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P189P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: CEBPA NM_004364.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21
• Publications: 2 publications found

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]

ENSG00000267727 (HGNC:):

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_004364.5

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004364.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	NM_004364.5	MANE Select	c.558_566dupGCCGCCGCC	p.Pro187_Pro189dup	disruptive_inframe_insertion	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.663_671dupGCCGCCGCC	p.Pro222_Pro224dup	disruptive_inframe_insertion	Exon 1 of 1	NP_001274353.1	P49715-4
	CEBPA	NM_001287435.2		c.516_524dupGCCGCCGCC	p.Pro173_Pro175dup	disruptive_inframe_insertion	Exon 1 of 1	NP_001274364.1	P49715-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	ENST00000498907.3	TSL:6 MANE Select	c.558_566dupGCCGCCGCC	p.Pro187_Pro189dup	disruptive_inframe_insertion	Exon 1 of 1	ENSP00000427514.1	P49715-1
	ENSG00000267727	ENST00000587312.1	TSL:3	n.403_411dupGGCGGCGGC		non_coding_transcript_exon	Exon 2 of 2
	CEBPA-DT	ENST00000718467.1		n.46+62_46+70dupGGCGGCGGC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000244

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000172 AC: 2 AN: 1162706 Hom.: 0 Cov.: 32 AF XY: 0.00000176 AC XY: 1 AN XY: 568590

African (AFR) AF: 0.00 AC: 0 AN: 23048

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16996

East Asian (EAS) AF: 0.00 AC: 0 AN: 23998

South Asian (SAS) AF: 0.0000208 AC: 1 AN: 48148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26508

Middle Eastern (MID) AF: 0.000320 AC: 1 AN: 3124

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 959906

Other (OTH) AF: 0.00 AC: 0 AN: 45694

GnomAD4 genome AF: 0.00000675 AC: 1 AN: 148062 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72100

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

African (AFR) AF: 0.0000244 AC: 1 AN: 40992

American (AMR) AF: 0.00 AC: 0 AN: 14940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66410

Other (OTH) AF: 0.00 AC: 0 AN: 2040

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Acute myeloid leukemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=88/12	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs746430067; hg19: chr19-33792754;