chr19-33302101-T-TCGCCGC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BP6BS2

The NM_004364.5(CEBPA):c.308_313dupGCGGCG(p.Gly103_Gly104dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000771 in 1,322,286 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D105D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

CEBPA
NM_004364.5 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 2.85

Publications

1 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:

ENSG00000267727 (HGNC:):

ENSG00000267727 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004364.5

BP6

Variant 19-33302101-T-TCGCCGC is Benign according to our data. Variant chr19-33302101-T-TCGCCGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456680.

BS2

High AC in GnomAd4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CEBPA	NM_004364.5 link	c.308_313dupGCGGCG	p.Gly103_Gly104dup	conservative_inframe_insertion	Exon 1 of 1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2 link	c.413_418dupGCGGCG	p.Gly138_Gly139dup	conservative_inframe_insertion	Exon 1 of 1		NP_001274353.1
CEBPA	NM_001287435.2 link	c.266_271dupGCGGCG	p.Gly89_Gly90dup	conservative_inframe_insertion	Exon 1 of 1		NP_001274364.1
CEBPA	NM_001285829.2 link	c.-50_-45dupGCGGCG		5_prime_UTR_variant	Exon 1 of 1		NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CEBPA	ENST00000498907.3 link	c.308_313dupGCGGCG	p.Gly103_Gly104dup	conservative_inframe_insertion	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1
CEBPA-DT	ENST00000718467.1 link	n.46+316_46+321dupGCCGCC		intron_variant	Intron 1 of 1
ENSG00000267727	ENST00000587312.1 link	n.161_162insCGCCGC		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000413

AC:

AN:

142988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00144

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000139

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000728

AC:

AN:

54968

AF XY:

0.0000928

show subpopulations

Gnomad AFR exome

AF:

0.00351

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:

0.000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000365

AC:

AN:

1179150

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

572106

show subpopulations

African (AFR)

AF:

0.00124

AC:

AN:

24108

American (AMR)

AF:

0.00

AC:

AN:

15606

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18770

East Asian (EAS)

AF:

0.00

AC:

AN:

26088

South Asian (SAS)

AF:

0.00

AC:

AN:

42040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39430

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3342

European-Non Finnish (NFE)

AF:

0.00000831

AC:

AN:

963136

Other (OTH)

AF:

0.000107

AC:

AN:

46630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

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

AF:

0.000412

AC:

AN:

143136

Hom.:

Cov.:

AF XY:

0.000401

AC XY:

AN XY:

69834

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

39634

American (AMR)

AF:

0.000139

AC:

AN:

14440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3392

East Asian (EAS)

AF:

0.00

AC:

AN:

4044

South Asian (SAS)

AF:

0.00

AC:

AN:

3882

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65626

Other (OTH)

AF:

0.00

AC:

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Acute myeloid leukemia

Uncertain:1Benign:1

Oct 04, 2022

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CEBPA c.308_313dup (p.Gly103_Gly104dup) change inserts six nucleotides at position 308-313 resulting in an in-frame duplication of two glycine residues. This variant has a maximum subpopulation frequency of 0.17% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/), however data at this position may not be reliable due to mean depth of coverage <30X. This variant has been reported in the literature in an individual with acute myeloid leukemia (PMID: 25468431). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Dec 16, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-frame insertion of 2 amino acids in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome

Uncertain:1

Dec 17, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Inborn genetic diseases

Benign:1

Mar 20, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.9

Mutation Taster

=79/21

polymorphism

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over