rs138859323

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014795.4(ZEB2):c.489C>T(p.Ile163Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,614,212 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 50 hom. )

Consequence

ZEB2
NM_014795.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.747

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:

ZEB2 (HGNC:):

ZEB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 2-144404939-G-A is Benign according to our data. Variant chr2-144404939-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144404939-G-A is described in Lovd as [Likely_benign]. Variant chr2-144404939-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.747 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB2	NM_014795.4 linkuse as main transcript	c.489C>T	p.Ile163Ile	synonymous_variant	5/10	ENST00000627532.3	NP_055610.1	O60315-1
ZEB2	NM_001171653.2 linkuse as main transcript	c.417C>T	p.Ile139Ile	synonymous_variant	4/9		NP_001165124.1	O60315-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3 linkuse as main transcript	c.489C>T	p.Ile163Ile	synonymous_variant	5/10	1	NM_014795.4	ENSP00000487174.1		O60315-1

Frequencies

GnomAD3 genomes

AF:

0.00299

AC:

455

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00536

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.00335

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00372

AC:

934

AN:

251314

Hom.:

AF XY:

0.00412

AC XY:

559

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00361

Gnomad ASJ exome

AF:

0.0192

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00376

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00392

Gnomad OTH exome

AF:

0.00684

GnomAD4 exome

AF:

0.00301

AC:

4406

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00326

AC XY:

2371

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00221

Gnomad4 AMR exome

AF:

0.00387

Gnomad4 ASJ exome

AF:

0.0199

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00402

Gnomad4 FIN exome

AF:

0.000880

Gnomad4 NFE exome

AF:

0.00230

Gnomad4 OTH exome

AF:

0.00588

GnomAD4 genome

AF:

0.00298

AC:

454

AN:

152340

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

219

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.0173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00335

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00448

Hom.:

Bravo

AF:

0.00311

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00583

EpiControl

AF:

0.00694

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2012	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	Sep 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 13, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2017	- -

Mowat-Wilson syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ZEB2: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2016

This alteration is classified as likely 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

Oct 25, 2023

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

BayesDel_noAF

Benign

-0.53

CADD

Benign

8.5

DANN

Benign

0.88

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