dbSNP rs752254340: CEBPA:p.Ala134Ala (chr19-33302013-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2

The NM_004364.5(CEBPA):c.402G>A(p.Ala134Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,180,674 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 9 hom. )

Consequence

CEBPA
NM_004364.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 0.0350

Publications

4 publications found

Variant links:

COSMIC-nc: COSV57196176

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:

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

CEBPA-DT links:

ENSG00000267727 (HGNC:):

ENSG00000267727 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 19-33302013-C-T is Benign according to our data. Variant chr19-33302013-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 239923.

BP7

Synonymous conserved (PhyloP=0.035 with no splicing effect.

BS2

High AC in GnomAd4 at 420 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	UniProt
CEBPA	NM_004364.5	MANE Select	c.402G>A	p.Ala134Ala	synonymous	Exon 1 of 1	NP_004355.2
CEBPA	NM_001287424.2		c.507G>A	p.Ala169Ala	synonymous	Exon 1 of 1	NP_001274353.1	P49715-4
CEBPA	NM_001287435.2		c.360G>A	p.Ala120Ala	synonymous	Exon 1 of 1	NP_001274364.1	P49715-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CEBPA	ENST00000498907.3	TSL:6 MANE Select	c.402G>A	p.Ala134Ala	synonymous	Exon 1 of 1	ENSP00000427514.1	P49715-1
CEBPA-DT	ENST00000718467.1		n.46+214C>T		intron	N/A
ENSG00000267727	ENST00000587312.1	TSL:3	n.*73C>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00283

AC:

420

AN:

148468

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000171

Gnomad AMI

AF:

0.0210

Gnomad AMR

AF:

0.00240

Gnomad ASJ

AF:

0.00411

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00572

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00429

Gnomad OTH

AF:

0.00147

GnomAD2 exomes

AF:

0.00187

AC:

AN:

2142

AF XY:

0.00176

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00235

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00266

AC:

2748

AN:

1032096

Hom.:

Cov.:

AF XY:

0.00272

AC XY:

1327

AN XY:

487920

show subpopulations

African (AFR)

AF:

0.000387

AC:

AN:

20678

American (AMR)

AF:

0.00121

AC:

AN:

6594

Ashkenazi Jewish (ASJ)

AF:

0.00387

AC:

AN:

11642

East Asian (EAS)

AF:

0.0000933

AC:

AN:

21442

South Asian (SAS)

AF:

0.00170

AC:

AN:

20574

European-Finnish (FIN)

AF:

0.00560

AC:

124

AN:

22130

Middle Eastern (MID)

AF:

0.000769

AC:

AN:

2602

European-Non Finnish (NFE)

AF:

0.00275

AC:

2443

AN:

886986

Other (OTH)

AF:

0.00205

AC:

AN:

39448

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

148

296

443

591

739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<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:

0.00283

AC:

420

AN:

148578

Hom.:

Cov.:

AF XY:

0.00304

AC XY:

220

AN XY:

72452

show subpopulations

African (AFR)

AF:

0.000170

AC:

AN:

41142

American (AMR)

AF:

0.00240

AC:

AN:

14998

Ashkenazi Jewish (ASJ)

AF:

0.00411

AC:

AN:

3406

East Asian (EAS)

AF:

0.00

AC:

AN:

5024

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00572

AC:

AN:

9272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00429

AC:

286

AN:

66658

Other (OTH)

AF:

0.00145

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00688

Hom.:

Bravo

AF:

0.00214

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Acute myeloid leukemia (1)

CEBPA-related disorder (1)

Hereditary cancer-predisposing syndrome (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

0.035

Mutation Taster

=98/2

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

Computational scores

Splicing

Publications

Other links and lift over