19-33302101-TCGCCGCCGC-TCGCCGCCGCCGCCGCCGC

Variant names:

• chr19-33302101-T-TCGCCGCCGC
• rs780345232
• NM_004364.5:c.305_313dupGCGGCGGCG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BP6

The NM_004364.5(CEBPA):​c.305_313dupGCGGCGGCG​(p.Gly102_Gly104dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000454 in 1,322,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D105D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: CEBPA NM_004364.5 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.85
• Publications: 1 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]

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

ENSG00000267727 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004364.5
• BP6: Variant 19-33302101-T-TCGCCGCCGC is Benign according to our data. Variant chr19-33302101-T-TCGCCGCCGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 937655.

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.305_313dupGCGGCGGCG	p.Gly102_Gly104dup	conservative_inframe_insertion	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.410_418dupGCGGCGGCG	p.Gly137_Gly139dup	conservative_inframe_insertion	Exon 1 of 1	NP_001274353.1	P49715-4
	CEBPA	NM_001287435.2		c.263_271dupGCGGCGGCG	p.Gly88_Gly90dup	conservative_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.305_313dupGCGGCGGCG	p.Gly102_Gly104dup	conservative_inframe_insertion	Exon 1 of 1	ENSP00000427514.1	P49715-1
	CEBPA-DT	ENST00000718467.1		n.46+313_46+321dupGCCGCCGCC		intron	N/A
	ENSG00000267727	ENST00000587312.1	TSL:3	n.*161_*162insCGCCGCCGC		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0000280 AC: 4 AN: 142988 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000759

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000694

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: 0.00000170 AC: 2 AN: 1179150 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 572106

African (AFR) AF: 0.00 AC: 0 AN: 24108

American (AMR) AF: 0.000128 AC: 2 AN: 15606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18770

East Asian (EAS) AF: 0.00 AC: 0 AN: 26088

South Asian (SAS) AF: 0.00 AC: 0 AN: 42040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3342

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 963136

Other (OTH) AF: 0.00 AC: 0 AN: 46630

GnomAD4 genome AF: 0.0000280 AC: 4 AN: 142988 Hom.: 0 Cov.: 32 AF XY: 0.0000574 AC XY: 4 AN XY: 69714

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

African (AFR) AF: 0.0000759 AC: 3 AN: 39540

American (AMR) AF: 0.0000694 AC: 1 AN: 14406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 4048

South Asian (SAS) AF: 0.00 AC: 0 AN: 3862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65626

Other (OTH) AF: 0.00 AC: 0 AN: 2026

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0240912), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Acute myeloid leukemia (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=79/21	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs780345232; hg19: chr19-33793007;