2-144399707-G-A

Position:

chr2-144399707-G-A

Variant summary

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

The ENST00000627532.3(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. 15/21 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
ENST00000627532.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.50

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=0.008516163).

BP6

Variant 2-144399707-G-A is Benign according to our data. Variant chr2-144399707-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144399707-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 300 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB2	NM_014795.4 linkuse as main transcript	c.1480C>T	p.Pro494Ser	missense_variant	8/10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2 linkuse as main transcript	c.1408C>T	p.Pro470Ser	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.1480C>T	p.Pro494Ser	missense_variant	8/10	1	NM_014795.4	ENSP00000487174	P4	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

GnomAD3 exomes

AF:

0.00200

AC:

501

AN:

251078

Hom.:

AF XY:

0.00203

AC XY:

276

AN XY:

135732

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 SAS 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

Gnomad4 AFR exome

AF:

0.000597

Gnomad4 AMR exome

AF:

0.00190

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00411

Gnomad4 OTH exome

AF:

0.00245

GnomAD4 genome

AF:

0.00197

AC:

300

AN:

152316

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00350

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00353

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

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 13, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	ZEB2: BP4, BS1 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 03, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jan 30, 2015	- -

Mowat-Wilson syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 06, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 06, 2019	This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: BP1,BP6. -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2018	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	Oct 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 09, 2014	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 22, 2019

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

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;.;.;.

MutationTaster

Benign

0.87

D;D;D;D

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

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