Genetic Variant NM_005194.4:c.221A>C (chr20-50191254-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005194.4(CEBPB):c.221A>C(p.Asp74Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000876 in 1,141,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.8e-7 ( 0 hom. )

Consequence

CEBPB
NM_005194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.21

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEBPB	NM_005194.4 link	c.221A>C	p.Asp74Ala	missense_variant	Exon 1 of 1	ENST00000303004.5	NP_005185.2	P17676-1
CEBPB	NM_001285878.1 link	c.152A>C	p.Asp51Ala	missense_variant	Exon 1 of 1		NP_001272807.1	P17676-2
CEBPB	NM_001285879.1 link	c.-374A>C		5_prime_UTR_variant	Exon 1 of 1		NP_001272808.1	P17676-3
CEBPB-AS1	NR_125739.1 link	n.561+14T>G		intron_variant	Intron 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEBPB	ENST00000303004.5 link	c.221A>C	p.Asp74Ala	missense_variant	Exon 1 of 1	6	NM_005194.4	ENSP00000305422.3		P17676-1
CEBPB-AS1	ENST00000613921.1 link	n.231+14T>G		intron_variant	Intron 1 of 5	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.76e-7

AC:

AN:

1141810

Hom.:

Cov.:

AF XY:

0.00000180

AC XY:

AN XY:

555494

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000105

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.221A>C (p.D74A) alteration is located in exon 1 (coding exon 1) of the CEBPB gene. This alteration results from a A to C substitution at nucleotide position 221, causing the aspartic acid (D) at amino acid position 74 to be replaced by an alanine (A). 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

Eigen

Benign

0.059

Eigen_PC

Benign

0.068

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.70

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

PrimateAI

Pathogenic

0.97

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.79

Vest4

0.57

MutPred

0.42

Loss of loop (P = 0.0986);

MVP

0.68

MPC

2.9

ClinPred

1.0

GERP RS

2.4

Varity_R

0.89

gMVP

0.74

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over