14-23118629-G-T

Variant names:

• chr14-23118629-G-T
• rs141903485
• NM_001805.4:c.463C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001805.4(CEBPE):​c.463C>A​(p.Leu155Met) variant causes a missense change. The variant allele was found at a frequency of 0.00715 in 1,611,416 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (44 hom.)
• Consequence: CEBPE NM_001805.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.91
• Publications: 12 publications found

Genes affected

CEBPE (HGNC:1836): (CCAAT enhancer binding protein epsilon) The protein encoded by this gene is a bZIP transcription factor which can bind as a homodimer to certain DNA regulatory regions. It can also form heterodimers with the related protein CEBP-delta. The encoded protein may be essential for terminal differentiation and functional maturation of committed granulocyte progenitor cells. Mutations in this gene have been associated with Specific Granule Deficiency, a rare congenital disorder. Multiple variants of this gene have been described, but the full-length nature of only one has been determined. [provided by RefSeq, Jul 2008]

CEBPE Gene-Disease associations (from GenCC):

• specific granule deficiency 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• specific granule deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000295888 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009663373).
• BP6: Variant 14-23118629-G-T is Benign according to our data. Variant chr14-23118629-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 530670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00534 (814/152328) while in subpopulation NFE AF = 0.00815 (554/68016). AF 95% confidence interval is 0.00758. There are 5 homozygotes in GnomAd4. There are 413 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001805.4. 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
	CEBPE	NM_001805.4	MANE Select	c.463C>A	p.Leu155Met	missense	Exon 1 of 2	NP_001796.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEBPE	ENST00000206513.6	TSL:1 MANE Select	c.463C>A	p.Leu155Met	missense	Exon 1 of 2	ENSP00000206513.5
	CEBPE	ENST00000696121.1		n.432C>A		non_coding_transcript_exon	Exon 2 of 3
	CEBPE	ENST00000696122.1		n.209C>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.00535 AC: 814 AN: 152210 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00814

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00606 AC: 1490 AN: 245940 AF XY: 0.00586

Gnomad AFR exome AF: 0.00128

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.000904

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0176

Gnomad NFE exome AF: 0.00936

Gnomad OTH exome AF: 0.00546

GnomAD4 exome AF: 0.00733 AC: 10700 AN: 1459088 Hom.: 44 Cov.: 32 AF XY: 0.00715 AC XY: 5190 AN XY: 726022

African (AFR) AF: 0.000896 AC: 30 AN: 33478

American (AMR) AF: 0.00105 AC: 47 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.000498 AC: 13 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86228

European-Finnish (FIN) AF: 0.0182 AC: 929 AN: 50910

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00839 AC: 9328 AN: 1111892

Other (OTH) AF: 0.00570 AC: 344 AN: 60326

GnomAD4 genome AF: 0.00534 AC: 814 AN: 152328 Hom.: 5 Cov.: 32 AF XY: 0.00554 AC XY: 413 AN XY: 74486

African (AFR) AF: 0.00130 AC: 54 AN: 41584

American (AMR) AF: 0.00189 AC: 29 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0153 AC: 162 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00815 AC: 554 AN: 68016

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00714 Hom.: 24

Bravo AF: 0.00413

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00647 AC: 785

EpiCase AF: 0.00665

EpiControl AF: 0.00711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CEBPE: BS2

Specific granule deficiency Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CEBPE-related disorder Benign:1

Nov 16, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.11
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.35
MVP		0.65
MPC		0.60
ClinPred		0.019	T
GERP RS		4.3
Varity_R		0.25
gMVP		0.38
Mutation Taster		=85/15	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: rs141903485; hg19: chr14-23587838; COSMIC: COSV99079624;