19-33301722-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004364.5(CEBPA):c.693C>G(p.Pro231=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,147,688 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P231P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0071 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (12 hom.)
• Consequence: CEBPA NM_004364.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.59

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-33301722-G-C is Benign according to our data. Variant chr19-33301722-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 415195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-33301722-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.59 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00714 (1059/148298) while in subpopulation AFR AF= 0.0246 (1010/41102). AF 95% confidence interval is 0.0233. There are 14 homozygotes in gnomad4. There are 502 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1056 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEBPA	NM_004364.5	c.693C>G	p.Pro231=	synonymous_variant	1/1	ENST00000498907.3
CEBPA	NM_001287424.2	c.798C>G	p.Pro266=	synonymous_variant	1/1
CEBPA	NM_001287435.2	c.651C>G	p.Pro217=	synonymous_variant	1/1
CEBPA	NM_001285829.2	c.336C>G	p.Pro112=	synonymous_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEBPA	ENST00000498907.3	c.693C>G	p.Pro231=	synonymous_variant	1/1		NM_004364.5	P1
	ENST00000587312.1	n.356+88G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00713 AC: 1056 AN: 148192 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00194

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.00392

GnomAD3 exomes AF: 0.00133 AC: 2 AN: 1506 Hom.: 0 AF XY: 0.00120 AC XY: 1 AN XY: 834

Gnomad AFR exome AF: 0.0357

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.000786 AC: 786 AN: 999390 Hom.: 12 Cov.: 29 AF XY: 0.000758 AC XY: 358 AN XY: 472284

Gnomad4 AFR exome AF: 0.0302

Gnomad4 AMR exome AF: 0.00279

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000158

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000920

Gnomad4 OTH exome AF: 0.00208

GnomAD4 genome AF: 0.00714 AC: 1059 AN: 148298 Hom.: 14 Cov.: 32 AF XY: 0.00694 AC XY: 502 AN XY: 72304

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.00194

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000150

Gnomad4 OTH AF: 0.00388

Alfa AF: 0.00437 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 15, 2018

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 14, 2020

- -

Acute myeloid leukemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	4.1
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs550308123; hg19: chr19-33792628; COSMIC: COSV105200113; COSMIC: COSV105200113;