chr19-33302051-C-G

Variant names:

• chr19-33302051-C-G
• rs1013724730
• NM_004364.5:c.364G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004364.5(CEBPA):​c.364G>C​(p.Gly122Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000898 in 1,202,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G122E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 2.53
• Publications: 2 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]

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

ENSG00000267727 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.12777963).
• BS2: High AC in GnomAd4 at 42 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	NM_004364.5	MANE Select	c.364G>C	p.Gly122Arg	missense	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.469G>C	p.Gly157Arg	missense	Exon 1 of 1	NP_001274353.1	P49715-4
	CEBPA	NM_001287435.2		c.322G>C	p.Gly108Arg	missense	Exon 1 of 1	NP_001274364.1	P49715-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	ENST00000498907.3	TSL:6 MANE Select	c.364G>C	p.Gly122Arg	missense	Exon 1 of 1	ENSP00000427514.1	P49715-1
	CEBPA-DT	ENST00000718467.1		n.46+252C>G		intron	N/A
	ENSG00000267727	ENST00000587312.1	TSL:3	n.*111C>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.000285 AC: 42 AN: 147210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000837

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000134

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: 0.0000752

Gnomad OTH AF: 0.000490

GnomAD4 exome AF: 0.0000625 AC: 66 AN: 1055222 Hom.: 0 Cov.: 33 AF XY: 0.0000600 AC XY: 30 AN XY: 500000

African (AFR) AF: 0.000944 AC: 20 AN: 21192

American (AMR) AF: 0.000431 AC: 3 AN: 6964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12312

East Asian (EAS) AF: 0.00 AC: 0 AN: 22700

South Asian (SAS) AF: 0.00 AC: 0 AN: 20224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2702

European-Non Finnish (NFE) AF: 0.0000478 AC: 43 AN: 899712

Other (OTH) AF: 0.00 AC: 0 AN: 40638

GnomAD4 genome AF: 0.000285 AC: 42 AN: 147340 Hom.: 0 Cov.: 32 AF XY: 0.000320 AC XY: 23 AN XY: 71920

African (AFR) AF: 0.000834 AC: 34 AN: 40752

American (AMR) AF: 0.000134 AC: 2 AN: 14898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 4774

South Asian (SAS) AF: 0.00 AC: 0 AN: 4524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000752 AC: 5 AN: 66508

Other (OTH) AF: 0.000485 AC: 1 AN: 2062

Alfa AF: 0.000498 Hom.: 0

Bravo AF: 0.000227

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	Acute myeloid leukemia (4)
-	1	-	CEBPA-related disorder (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	23
DANN	Benign	0.91
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.029
Sift	Benign	0.35	T
Sift4G	Benign	0.20	T
Polyphen		0.012	B
Vest4		0.22
MutPred		0.30		Gain of solvent accessibility (P = 0.0037)
MVP		0.26
ClinPred		0.13	T
GERP RS		3.6
PromoterAI		-0.013	Neutral
Varity_R		0.094
gMVP		0.17
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs1013724730; hg19: chr19-33792957;