Genetic Variant CEBPA:p.Gly32Cys (chr19-33302321-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001285829.2(CEBPA):c.-264G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000803 in 1,245,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

CEBPA
NM_001285829.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.944

Publications

3 publications found

Variant links:

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30144286).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001285829.2. 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.94G>T	p.Gly32Cys	missense	Exon 1 of 1	NP_004355.2
CEBPA	NM_001285829.2		c.-264G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 1	NP_001272758.1	P49715-3
CEBPA	NM_001287424.2		c.199G>T	p.Gly67Cys	missense	Exon 1 of 1	NP_001274353.1	P49715-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	ENST00000498907.3	TSL:6 MANE Select	c.94G>T	p.Gly32Cys	missense	Exon 1 of 1	ENSP00000427514.1	P49715-1
	CEBPA-DT	ENST00000718467.1		n.46+522C>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000219

AC:

AN:

45764

AF XY:

0.0000376

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000642

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

8.03e-7

AC:

AN:

1245064

Hom.:

Cov.:

AF XY:

0.00000164

AC XY:

AN XY:

610824

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24660

American (AMR)

AF:

0.00

AC:

AN:

14984

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18322

East Asian (EAS)

AF:

0.00

AC:

AN:

27522

South Asian (SAS)

AF:

0.00

AC:

AN:

56170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4850

European-Non Finnish (NFE)

AF:

9.95e-7

AC:

AN:

1004752

Other (OTH)

AF:

0.00

AC:

AN:

50230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.086

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.87

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.4

PhyloP100

0.94

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-1.4

REVEL

Benign

0.13

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.0060

Polyphen

0.59

Vest4

0.28

MutPred

0.22

Loss of methylation at R35 (P = 0.0806)

MVP

0.39

ClinPred

0.25

GERP RS

3.9

PromoterAI

-0.032

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.24

gMVP

0.38

Mutation Taster

=76/24

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over