dbSNP rs535980233: CEBPA:p.Gly223Cys (chr19-33301748-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004364.5(CEBPA):c.667G>T(p.Gly223Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G223S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CEBPA
NM_004364.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.14

Publications

5 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:

ENSG00000267727 (HGNC:):

ENSG00000267727 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.667G>T	p.Gly223Cys	missense	Exon 1 of 1	NP_004355.2
CEBPA	NM_001287424.2		c.772G>T	p.Gly258Cys	missense	Exon 1 of 1	NP_001274353.1
CEBPA	NM_001287435.2		c.625G>T	p.Gly209Cys	missense	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.667G>T	p.Gly223Cys	missense	Exon 1 of 1	ENSP00000427514.1
ENSG00000267727	ENST00000587312.1	TSL:3	n.357-67C>A		intron	N/A
CEBPA-DT	ENST00000718467.1		n.-6C>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1017610

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

482100

African (AFR)

AF:

0.00

AC:

AN:

20340

American (AMR)

AF:

0.00

AC:

AN:

6330

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11358

East Asian (EAS)

AF:

0.00

AC:

AN:

20414

South Asian (SAS)

AF:

0.00

AC:

AN:

20376

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2612

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

878842

Other (OTH)

AF:

0.00

AC:

AN:

38800

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

Eigen

Benign

0.033

Eigen_PC

Benign

-0.036

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.84

MetaRNN

Uncertain

0.55

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

5.1

PrimateAI

Pathogenic

0.94

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.26

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.37

MutPred

0.17

Gain of catalytic residue at P222 (P = 0.0073)

MVP

0.44

ClinPred

0.99

GERP RS

3.0

Varity_R

0.62

gMVP

0.56

Mutation Taster

=80/20

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over