rs112005830

Positions:

chr2-144398957-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The ENST00000627532.3(ZEB2):c.2230A>G(p.Ile744Val) variant causes a missense change. The variant allele was found at a frequency of 0.00113 in 1,614,180 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 8 hom. )

Consequence

ZEB2
ENST00000627532.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.11

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ZEB2. . Gene score misZ 3.9433 (greater than the threshold 3.09). Trascript score misZ 5.6227 (greater than threshold 3.09). GenCC has associacion of gene with Mowat-Wilson syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.007555723).

BP6

Variant 2-144398957-T-C is Benign according to our data. Variant chr2-144398957-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 95630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398957-T-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 168 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB2	NM_014795.4 linkuse as main transcript	c.2230A>G	p.Ile744Val	missense_variant	8/10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2 linkuse as main transcript	c.2158A>G	p.Ile720Val	missense_variant	7/9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3 linkuse as main transcript	c.2230A>G	p.Ile744Val	missense_variant	8/10	1	NM_014795.4	ENSP00000487174	P4	O60315-1

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

168

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00829

Gnomad FIN

AF:

0.00565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00198

AC:

497

AN:

251394

Hom.:

AF XY:

0.00244

AC XY:

331

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00823

Gnomad FIN exome

AF:

0.00536

Gnomad NFE exome

AF:

0.000976

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00114

AC:

1660

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

1012

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00810

Gnomad4 FIN exome

AF:

0.00425

Gnomad4 NFE exome

AF:

0.000572

Gnomad4 OTH exome

AF:

0.00103

GnomAD4 genome

AF:

0.00110

AC:

168

AN:

152300

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

105

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00829

Gnomad4 FIN

AF:

0.00565

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000827

Hom.:

Bravo

AF:

0.000487

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00207

AC:

251

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.000948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 10, 2013	- -

Mowat-Wilson syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ZEB2: BS1 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 22, 2016	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2016

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2019

This variant is classified as 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

0.086

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0090

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

Eigen

Benign

-0.052

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.90

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

M_CAP

Benign

0.0044

MetaRNN

Benign

0.0076

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.32

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

REVEL

Benign

0.080

Sift

Benign

0.54

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

Sift4G

Benign

0.36

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

Polyphen

0.031

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

Vest4

0.43, 0.47, 0.44, 0.44, 0.43

MVP

0.18

MPC

0.62

ClinPred

0.016

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.22

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