2-144517342-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_014795.4(ZEB2):c.9G>C(p.Gln3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,613,638 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q3Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00015 ( 3 hom. )

Consequence

ZEB2
NM_014795.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.45

Publications

4 publications found

Variant links:

COSMIC-nc: COSV57969754

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023572057).

BP6

Variant 2-144517342-C-G is Benign according to our data. Variant chr2-144517342-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 160332.

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4 link	c.9G>C	p.Gln3His	missense_variant	Exon 2 of 10	ENST00000627532.3	NP_055610.1	O60315-1
ZEB2	NM_001171653.2 link	c.9G>C	p.Gln3His	missense_variant	Exon 2 of 9		NP_001165124.1	O60315-2
ZEB2	NR_033258.2 link	n.259G>C		non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3 link	c.9G>C	p.Gln3His	missense_variant	Exon 2 of 10	1	NM_014795.4	ENSP00000487174.1		O60315-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00213

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000269

AC:

AN:

249258

AF XY:

0.000311

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00191

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000149

AC:

218

AN:

1461402

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

131

AN XY:

727000

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00249

AC:

AN:

39692

South Asian (SAS)

AF:

0.00114

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111864

Other (OTH)

AF:

0.000315

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000145

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41552

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00213

AC:

AN:

5156

South Asian (SAS)

AF:

0.00228

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2114

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:

0.00

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.000321

AC:

Asia WGS

AF:

0.00407

AC:

AN:

3454

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 30, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 06, 2016

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. -

Mowat-Wilson syndrome

Benign:2

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: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

- -

Inborn genetic diseases

Uncertain:1

Dec 02, 2016

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Q3H variant (also known as c.9G>C), located in coding exon 1 of the ZEB2 gene, results from a G to C substitution at nucleotide position 9. The glutamine at codon 3 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on data from ExAC, the C allele has an overall frequency of approximately 0.034% (36/105,942) total alleles studied (TCGA excluded). The highest observed frequency was 0.216% (17/7,854) of East Asian alleles. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

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

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.024

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

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.5

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

PhyloP100

2.4

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.52

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

REVEL

Benign

0.27

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.015

.;D;D;D;.;D;D;D;.;.;D;.;T;.;.;T;.;T;T;T;T

Polyphen

0.0, 0.58

.;B;.;B;.;.;B;.;.;.;.;.;.;.;P;.;.;.;.;.;.

Vest4

0.36, 0.38, 0.34, 0.34, 0.34, 0.36, 0.35, 0.45, 0.34

MutPred

0.13

Loss of solvent accessibility (P = 0.0635);Loss of solvent accessibility (P = 0.0635);Loss of solvent accessibility (P = 0.0635);Loss of solvent accessibility (P = 0.0635);Loss of solvent accessibility (P = 0.0635);Loss of solvent accessibility (P = 0.0635);Loss of solvent accessibility (P = 0.0635);Loss of solvent accessibility (P = 0.0635);.;Loss of solvent accessibility (P = 0.0635);.;Loss of solvent accessibility (P = 0.0635);Loss of solvent accessibility (P = 0.0635);Loss of solvent accessibility (P = 0.0635);Loss of solvent accessibility (P = 0.0635);Loss of solvent accessibility (P = 0.0635);Loss of solvent accessibility (P = 0.0635);Loss of solvent accessibility (P = 0.0635);.;Loss of solvent accessibility (P = 0.0635);Loss of solvent accessibility (P = 0.0635);

MVP

0.53

MPC

0.85

ClinPred

0.039

GERP RS

1.8

PromoterAI

-0.062

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.16

gMVP

0.51

Mutation Taster

=98/2

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