19-33301825-GGCGGGTGCGGGT-GGCGGGTGCGGGTGCGGGT

Position:

• chr19-33301825-GGCGGGTGCGGGT-GGCGGGTGCGGGTGCGGGT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004364.5(CEBPA):​c.584_589dupACCCGC​(p.His195_Pro196dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,262,426 control chromosomes in the GnomAD database, including 862 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (148 hom., cov: 31)
  • Exomes 𝑓: 0.027 (714 hom.)
• Consequence: CEBPA NM_004364.5 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.645

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:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 19-33301825-G-GGCGGGT is Benign according to our data. Variant chr19-33301825-G-GGCGGGT is described in ClinVar as [Likely_benign]. Clinvar id is 210652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.584_589dupACCCGC	p.His195_Pro196dup	conservative_inframe_insertion	1/1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2	c.689_694dupACCCGC	p.His230_Pro231dup	conservative_inframe_insertion	1/1		NP_001274353.1
CEBPA	NM_001287435.2	c.542_547dupACCCGC	p.His181_Pro182dup	conservative_inframe_insertion	1/1		NP_001274364.1
CEBPA	NM_001285829.2	c.227_232dupACCCGC	p.His76_Pro77dup	conservative_inframe_insertion	1/1		NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3	c.584_589dupACCCGC	p.His195_Pro196dup	conservative_inframe_insertion	1/1	6	NM_004364.5	ENSP00000427514.1
ENSG00000267727	ENST00000587312.1	n.383_388dupGGTGCG		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0374 AC: 5544 AN: 148140 Hom.: 147 Cov.: 31

Gnomad AFR AF: 0.0439

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.0410

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.0364

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.0449

Gnomad NFE AF: 0.0265

Gnomad OTH AF: 0.0348

GnomAD3 exomes AF: 0.00845 AC: 86 AN: 10180 Hom.: 0 AF XY: 0.0100 AC XY: 65 AN XY: 6468

Gnomad AFR exome AF: 0.00538

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.0345

Gnomad SAS exome AF: 0.0136

Gnomad FIN exome AF: 0.00532

Gnomad NFE exome AF: 0.00666

Gnomad OTH exome AF: 0.00649

GnomAD4 exome AF: 0.0270 AC: 30091 AN: 1114178 Hom.: 714 Cov.: 27 AF XY: 0.0269 AC XY: 14545 AN XY: 540890

Gnomad4 AFR exome AF: 0.0402

Gnomad4 AMR exome AF: 0.0429

Gnomad4 ASJ exome AF: 0.0300

Gnomad4 EAS exome AF: 0.194

Gnomad4 SAS exome AF: 0.0284

Gnomad4 FIN exome AF: 0.0205

Gnomad4 NFE exome AF: 0.0222

Gnomad4 OTH exome AF: 0.0317

GnomAD4 genome AF: 0.0374 AC: 5540 AN: 148248 Hom.: 148 Cov.: 31 AF XY: 0.0378 AC XY: 2730 AN XY: 72278

Gnomad4 AFR AF: 0.0438

Gnomad4 AMR AF: 0.0409

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.159

Gnomad4 SAS AF: 0.0364

Gnomad4 FIN AF: 0.0185

Gnomad4 NFE AF: 0.0265

Gnomad4 OTH AF: 0.0354

Asia WGS AF: 0.0710 AC: 213 AN: 3016

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2020	In-frame insertion of 2 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 23926458, 29365323, 18729193, 25987038, 17190859, 29410295, 24054719, 20970189, 29668487, 29727824, 21403128, 28637622, 17557966, 15746035, 17851556, 14726504, 22389883, 18946494, 27602952, 29180507, 24056881, 25468431) -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 17, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 24, 2015	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Jun 10, 2020

- -

Acute myeloid leukemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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: rs762459325; hg19: chr19-33792731;