19-33301825-GGCGGGTGCGGGT-GGCGGGTGCGGGTGCGGGT

Variant names:

• chr19-33301825-G-GGCGGGT
• rs762459325
• NM_004364.5:c.584_589dupACCCGC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P197P) has been classified 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:9
• Conservation: PhyloP100: 0.645
• Publications: 22 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004364.5
• BP6: Variant 19-33301825-G-GGCGGGT is Benign according to our data. Variant chr19-33301825-G-GGCGGGT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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.

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.584_589dupACCCGC	p.His195_Pro196dup	conservative_inframe_insertion	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.689_694dupACCCGC	p.His230_Pro231dup	conservative_inframe_insertion	Exon 1 of 1	NP_001274353.1	P49715-4
	CEBPA	NM_001287435.2		c.542_547dupACCCGC	p.His181_Pro182dup	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.584_589dupACCCGC	p.His195_Pro196dup	conservative_inframe_insertion	Exon 1 of 1	ENSP00000427514.1	P49715-1
	ENSG00000267727	ENST00000587312.1	TSL:3	n.383_388dupGGTGCG		non_coding_transcript_exon	Exon 2 of 2
	CEBPA-DT	ENST00000718467.1		n.46+42_46+47dupGGTGCG		intron	N/A

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

GnomAD2 exomes AF: 0.00845 AC: 86 AN: 10180 AF XY: 0.0100

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 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

African (AFR) AF: 0.0402 AC: 883 AN: 21960

American (AMR) AF: 0.0429 AC: 378 AN: 8812

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 417 AN: 13898

East Asian (EAS) AF: 0.194 AC: 4577 AN: 23602

South Asian (SAS) AF: 0.0284 AC: 1036 AN: 36502

European-Finnish (FIN) AF: 0.0205 AC: 490 AN: 23934

Middle Eastern (MID) AF: 0.0414 AC: 119 AN: 2872

European-Non Finnish (NFE) AF: 0.0222 AC: 20808 AN: 938992

Other (OTH) AF: 0.0317 AC: 1383 AN: 43606

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

African (AFR) AF: 0.0438 AC: 1798 AN: 41076

American (AMR) AF: 0.0409 AC: 612 AN: 14976

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 108 AN: 3402

East Asian (EAS) AF: 0.159 AC: 793 AN: 4974

South Asian (SAS) AF: 0.0364 AC: 175 AN: 4804

European-Finnish (FIN) AF: 0.0185 AC: 170 AN: 9206

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.0265 AC: 1764 AN: 66550

Other (OTH) AF: 0.0354 AC: 73 AN: 2060

Alfa AF: 0.0101 Hom.: 5

Asia WGS AF: 0.0710 AC: 213 AN: 3016

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Acute myeloid leukemia (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.65
Mutation Taster		=74/26	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs762459325; hg19: chr19-33792731; COSMIC: COSV57196906; COSMIC: COSV57196906;