Genetic Variant CEBPB:p.Pro49Leu (chr20-50191179-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005194.4(CEBPB):c.146C>T(p.Pro49Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000346 in 1,443,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CEBPB
NM_005194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.916

Variant links:

Genes affected

CEBPB (HGNC:1834): (CCAAT enhancer binding protein beta) This intronless gene encodes a transcription factor that contains a basic leucine zipper (bZIP) domain. The encoded protein functions as a homodimer but can also form heterodimers with CCAAT/enhancer-binding proteins alpha, delta, and gamma. Activity of this protein is important in the regulation of genes involved in immune and inflammatory responses, among other processes. The use of alternative in-frame AUG start codons results in multiple protein isoforms, each with distinct biological functions. [provided by RefSeq, Oct 2013]

CEBPB links:

CEBPB-AS1 (HGNC:51226): (CEBPB antisense RNA 1)

CEBPB-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12145406).

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPB	NM_005194.4 link	c.146C>T	p.Pro49Leu	missense_variant	Exon 1 of 1	ENST00000303004.5	NP_005185.2	P17676-1
CEBPB	NM_001285878.1 link	c.77C>T	p.Pro26Leu	missense_variant	Exon 1 of 1		NP_001272807.1	P17676-2
CEBPB	NM_001285879.1 link	c.-449C>T		5_prime_UTR_variant	Exon 1 of 1		NP_001272808.1	P17676-3
CEBPB-AS1	NR_125739.1 link	n.561+89G>A		intron_variant	Intron 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEBPB	ENST00000303004.5 link	c.146C>T	p.Pro49Leu	missense_variant	Exon 1 of 1	6	NM_005194.4	ENSP00000305422.3		P17676-1
CEBPB-AS1	ENST00000613921.1 link	n.231+89G>A		intron_variant	Intron 1 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.000179

AC:

AN:

151104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000653

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1292426

Hom.:

Cov.:

AF XY:

0.00000940

AC XY:

AN XY:

638170

show subpopulations

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.72e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000179

AC:

AN:

151104

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

AN XY:

73750

show subpopulations

Gnomad4 AFR

AF:

0.000653

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000253

ExAC

AF:

0.0000113

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.146C>T (p.P49L) alteration is located in exon 1 (coding exon 1) of the CEBPB gene. This alteration results from a C to T substitution at nucleotide position 146, causing the proline (P) at amino acid position 49 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.38

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.55

M_CAP

Benign

0.051

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.0

REVEL

Benign

0.028

Sift

Benign

0.12

Sift4G

Uncertain

0.047

Polyphen

0.019

Vest4

0.19

MutPred

0.31

Loss of glycosylation at P49 (P = 0.0129);

MVP

0.45

MPC

2.3

ClinPred

0.18

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.078

gMVP

0.26

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over