19-33301781-G-C

Variant names:

• chr19-33301781-G-C
• rs1433126196
• NM_004364.5:c.634C>G

Variant summary

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

The NM_004364.5(CEBPA):​c.634C>G​(p.His212Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H212P) 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: 7.08
• 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]

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

ENSG00000267727 (HGNC:):

ACMG classification

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	NM_004364.5	MANE Select	c.634C>G	p.His212Asp	missense	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.739C>G	p.His247Asp	missense	Exon 1 of 1	NP_001274353.1
	CEBPA	NM_001287435.2		c.592C>G	p.His198Asp	missense	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.634C>G	p.His212Asp	missense	Exon 1 of 1	ENSP00000427514.1
	CEBPA-DT	ENST00000718467.1		n.28G>C		non_coding_transcript_exon	Exon 1 of 2
	ENSG00000267727	ENST00000587312.1	TSL:3	n.357-34G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 22

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

Dec 14, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine with aspartic acid at codon 212 of the CEBPA protein (p.His212Asp). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and aspartic acid. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with CEBPA-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.1
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.24
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.73	T
Polyphen		0.98	D
Vest4		0.48
MutPred		0.16		Loss of sheet (P = 0.0457)
MVP		0.27
ClinPred		0.94	D
GERP RS		4.0
Varity_R		0.50
gMVP		0.44
Mutation Taster		=77/23	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: rs1433126196; hg19: chr19-33792687;