19-33302346-CG-CGG
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004364.5(CEBPA):c.68dupC(p.His24AlafsTer84) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000335 in 1,195,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000033 ( 0 hom. )
Consequence
CEBPA
NM_004364.5 frameshift
NM_004364.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.177
Publications
24 publications found
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]
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 62 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-33302346-C-CG is Pathogenic according to our data. Variant chr19-33302346-C-CG is described in ClinVar as Pathogenic. ClinVar VariationId is 21401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CEBPA | NM_004364.5 | MANE Select | c.68dupC | p.His24AlafsTer84 | frameshift | Exon 1 of 1 | NP_004355.2 | ||
| CEBPA | NM_001287424.2 | c.173dupC | p.His59AlafsTer84 | frameshift | Exon 1 of 1 | NP_001274353.1 | |||
| CEBPA | NM_001287435.2 | c.26dupC | p.His10AlafsTer84 | frameshift | Exon 1 of 1 | NP_001274364.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CEBPA | ENST00000498907.3 | TSL:6 MANE Select | c.68dupC | p.His24AlafsTer84 | frameshift | Exon 1 of 1 | ENSP00000427514.1 | ||
| CEBPA-DT | ENST00000718467.1 | n.46+553dupG | intron | N/A |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000335 AC: 4AN: 1195068Hom.: 0 Cov.: 32 AF XY: 0.00000344 AC XY: 2AN XY: 581784 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
4
AN:
1195068
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
581784
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
23518
American (AMR)
AF:
AC:
0
AN:
9378
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
15568
East Asian (EAS)
AF:
AC:
0
AN:
27212
South Asian (SAS)
AF:
AC:
1
AN:
44676
European-Finnish (FIN)
AF:
AC:
0
AN:
40342
Middle Eastern (MID)
AF:
AC:
0
AN:
4474
European-Non Finnish (NFE)
AF:
AC:
3
AN:
981854
Other (OTH)
AF:
AC:
0
AN:
48046
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<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
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Acute myeloid leukemia Pathogenic:1Other:1
Genomic Diagnostics Laboratory, National Institute of Medical Genomics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The variant was detected in bone marrow from patients, but it was not confirmed in the matched
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only
not provided Pathogenic:1
Dec 15, 2017
Clinical Genetics and Genomics, Karolinska University Hospital
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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