Genetic Variant NM_004364.5:c.693C>G (chr19-33301722-G-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004364.5(CEBPA):c.693C>G(p.Pro231Pro) 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.59

Publications

2 publications found

Variant links:

COSMIC-nc: COSV105200113

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 links:

ENSG00000267727 (HGNC:):

ENSG00000267727 links:

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

CEBPA-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 415195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1059 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEBPA	NM_004364.5	MANE Select	c.693C>G	p.Pro231Pro	synonymous	Exon 1 of 1	NP_004355.2
CEBPA	NM_001287424.2		c.798C>G	p.Pro266Pro	synonymous	Exon 1 of 1	NP_001274353.1
CEBPA	NM_001287435.2		c.651C>G	p.Pro217Pro	synonymous	Exon 1 of 1	NP_001274364.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEBPA	ENST00000498907.3	TSL:6 MANE Select	c.693C>G	p.Pro231Pro	synonymous	Exon 1 of 1	ENSP00000427514.1
ENSG00000267727	ENST00000587312.1	TSL:3	n.356+88G>C		intron	N/A
CEBPA-DT	ENST00000718467.1		n.-32G>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00713

AC:

1056

AN:

148192

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00133

AC:

AN:

1506

AF XY:

0.00120

show subpopulations

Gnomad AFR exome

AF:

0.0357

Gnomad AMR exome

AF:

0.00

Gnomad ASJ 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.:

Cov.:

AF XY:

0.000758

AC XY:

358

AN XY:

472284

show subpopulations

African (AFR)

AF:

0.0302

AC:

603

AN:

19956

American (AMR)

AF:

0.00279

AC:

AN:

5728

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10448

East Asian (EAS)

AF:

0.00

AC:

AN:

17860

South Asian (SAS)

AF:

0.000158

AC:

AN:

19014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16690

Middle Eastern (MID)

AF:

0.00222

AC:

AN:

2698

European-Non Finnish (NFE)

AF:

0.0000920

AC:

AN:

869528

Other (OTH)

AF:

0.00208

AC:

AN:

37468

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.566

Heterozygous variant carriers

128

160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00714

AC:

1059

AN:

148298

Hom.:

Cov.:

AF XY:

0.00694

AC XY:

502

AN XY:

72304

show subpopulations

African (AFR)

AF:

0.0246

AC:

1010

AN:

41102

American (AMR)

AF:

0.00194

AC:

AN:

14956

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3406

East Asian (EAS)

AF:

0.00

AC:

AN:

5092

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9124

Middle Eastern (MID)

AF:

0.00690

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000150

AC:

AN:

66554

Other (OTH)

AF:

0.00388

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00437

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Dec 14, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Nov 15, 2018

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Oct 02, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Acute myeloid leukemia

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

4.1

(source)

DANN

Benign

0.64

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over