chr19-33301854-C-T

Variant names:

• chr19-33301854-C-T
• rs538441046
• NM_004364.5:c.561G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001287424.2(CEBPA):​c.666G>A​(p.Pro222Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000442 in 1,131,288 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P222P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: CEBPA NM_001287424.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.330
• Publications: 1 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP7: Synonymous conserved (PhyloP=0.33 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001287424.2. 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.561G>A	p.Pro187Pro	synonymous	Exon 1 of 1	NP_004355.2
	CEBPA	NM_001287424.2		c.666G>A	p.Pro222Pro	synonymous	Exon 1 of 1	NP_001274353.1
	CEBPA	NM_001287435.2		c.519G>A	p.Pro173Pro	synonymous	Exon 1 of 1	NP_001274364.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPA	ENST00000498907.3	TSL:6 MANE Select	c.561G>A	p.Pro187Pro	synonymous	Exon 1 of 1	ENSP00000427514.1
	ENSG00000267727	ENST00000587312.1	TSL:3	n.396C>T		non_coding_transcript_exon	Exon 2 of 2
	CEBPA-DT	ENST00000718467.1		n.46+55C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000233 AC: 1 AN: 42962 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.0000638

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000442 AC: 5 AN: 1131288 Hom.: 0 Cov.: 32 AF XY: 0.00000361 AC XY: 2 AN XY: 553432

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21878

American (AMR) AF: 0.00 AC: 0 AN: 14638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15782

East Asian (EAS) AF: 0.00 AC: 0 AN: 20674

South Asian (SAS) AF: 0.0000208 AC: 1 AN: 47980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2936

European-Non Finnish (NFE) AF: 0.00000426 AC: 4 AN: 939752

Other (OTH) AF: 0.00 AC: 0 AN: 43358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000529729), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs538441046; hg19: chr19-33792760;