19-33301691-C-G

Variant names:

• chr19-33301691-C-G
• rs530569305
• NM_004364.5:c.724G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_004364.5(CEBPA):​c.724G>C​(p.Gly242Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G242S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEBPA NM_004364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.617
• Publications: 0 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]

ENSG00000267727 (HGNC:):

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26339364).
• BP6: Variant 19-33301691-C-G is Benign according to our data. Variant chr19-33301691-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1935493.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPA	NM_004364.5	c.724G>C	p.Gly242Arg	missense_variant	Exon 1 of 1	ENST00000498907.3	NP_004355.2
CEBPA	NM_001287424.2	c.829G>C	p.Gly277Arg	missense_variant	Exon 1 of 1		NP_001274353.1
CEBPA	NM_001287435.2	c.682G>C	p.Gly228Arg	missense_variant	Exon 1 of 1		NP_001274364.1
CEBPA	NM_001285829.2	c.367G>C	p.Gly123Arg	missense_variant	Exon 1 of 1		NP_001272758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEBPA	ENST00000498907.3	c.724G>C	p.Gly242Arg	missense_variant	Exon 1 of 1	6	NM_004364.5	ENSP00000427514.1
ENSG00000267727	ENST00000587312.1	n.356+57C>G		intron_variant	Intron 1 of 1	3
CEBPA-DT	ENST00000718467.1	n.-63C>G		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acute myeloid leukemia Uncertain:1

Oct 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 242 of the CEBPA protein (p.Gly242Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CEBPA-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.76
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.62
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.072
Sift	Benign	0.29	T
Sift4G	Benign	0.54	T
Polyphen		0.87	P
Vest4		0.30
MutPred		0.27		Gain of solvent accessibility (P = 0.0055);
MVP		0.42
ClinPred		0.14	T
GERP RS		3.2
Varity_R		0.085
gMVP		0.34
Mutation Taster		=95/5	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: rs530569305; hg19: chr19-33792597;