rs144952836

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014795.4(ZEB2):c.1480C>T(p.Pro494Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00318 in 1,614,138 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P494P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 7 hom. )

Consequence

ZEB2
NM_014795.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 4.50

Publications

7 publications found

Variant links:

COSMIC-nc: COSV106060858

Genes affected

ZEB2 (HGNC:14881): (zinc finger E-box binding homeobox 2) The protein encoded by this gene is a member of the Zfh1 family of 2-handed zinc finger/homeodomain proteins. It is located in the nucleus and functions as a DNA-binding transcriptional repressor that interacts with activated SMADs. Mutations in this gene are associated with Hirschsprung disease/Mowat-Wilson syndrome. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jan 2010]

ZEB2 Gene-Disease associations (from GenCC):

Mowat-Wilson syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ZEB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008516163).

BP6

Variant 2-144399707-G-A is Benign according to our data. Variant chr2-144399707-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 300 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4 link	c.1480C>T	p.Pro494Ser	missense_variant	Exon 8 of 10	ENST00000627532.3	NP_055610.1	O60315-1
ZEB2	NM_001171653.2 link	c.1408C>T	p.Pro470Ser	missense_variant	Exon 7 of 9		NP_001165124.1	O60315-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3 link	c.1480C>T	p.Pro494Ser	missense_variant	Exon 8 of 10	1	NM_014795.4	ENSP00000487174.1		O60315-1

Frequencies

GnomAD3 genomes

AF:

0.00197

AC:

300

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

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:

0.00350

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00200

AC:

501

AN:

251078

AF XY:

0.00203

show subpopulations

Gnomad AFR exome

AF:

0.000740

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00362

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00331

AC:

4833

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00324

AC XY:

2354

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.000597

AC:

AN:

33474

American (AMR)

AF:

0.00190

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00411

AC:

4565

AN:

1111978

Other (OTH)

AF:

0.00245

AC:

148

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

314

628

942

1256

1570

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

174

348

522

696

870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00197

AC:

300

AN:

152316

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

41568

American (AMR)

AF:

0.00183

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00350

AC:

238

AN:

68028

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00316

Hom.:

Bravo

AF:

0.00224

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00199

AC:

242

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00393

EpiControl

AF:

0.00362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Jan 03, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ZEB2: PP2, BP4, BS1 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 13, 2016

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 30, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mowat-Wilson syndrome

Benign:5

Mar 06, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: BP1,BP6. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Oct 13, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 09, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 08, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases

Benign:1

Jun 13, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ZEB2-related disorder

Benign:1

Dec 22, 2019

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.0016

T;T;T;T;T;.;T;T;T;T;.;T;T;T;.

Eigen

Benign

-0.097

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

.;.;.;.;D;D;D;.;.;D;D;D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.0085

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.2

.;.;.;.;.;.;.;L;L;.;.;L;.;.;.

PhyloP100

4.5

PrimateAI

Benign

0.39

PROVEAN

Benign

0.030

.;.;.;.;.;.;.;.;N;.;N;N;.;.;.

REVEL

Benign

0.21

Sift

Benign

0.93

.;.;.;.;.;.;.;.;T;.;T;T;.;.;.

Sift4G

Benign

0.65

.;.;.;.;.;.;.;T;T;.;T;T;T;.;.

Polyphen

0.0030, 0.0

.;.;.;.;.;.;.;B;B;.;.;B;B;.;.

Vest4

0.12, 0.070, 0.079, 0.10, 0.086

MVP

0.33

MPC

0.71

ClinPred

0.019

GERP RS

5.7

Varity_R

0.030

gMVP

0.29

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over