rs144952836

chr2-144399707-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

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. 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 NM_014795.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 4.50

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ZEB2
• 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 GnomAd at 300 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZEB2	NM_014795.4	c.1480C>T	p.Pro494Ser	missense_variant	8/10	ENST00000627532.3
ZEB2	NM_001171653.2	c.1408C>T	p.Pro470Ser	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZEB2	ENST00000627532.3	c.1480C>T	p.Pro494Ser	missense_variant	8/10	1	NM_014795.4	P4

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152198 Hom.: 2 Cov.: 32

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.: 0 AF XY: 0.00203 AC XY: 276 AN XY: 135732

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.: 7 Cov.: 32 AF XY: 0.00324 AC XY: 2354 AN XY: 727210

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.: 2 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74474

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.: 2

Bravo AF: 0.00224

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00199 AC: 242

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

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, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jan 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	ZEB2: BP4, BS1 -

Mowat-Wilson syndrome Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 06, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 13, 2017	- -
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	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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	21
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	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0085	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	0.87	D;D;D;D
PrimateAI	Benign	0.39	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	T
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

Other links and lift over

dbSNP: rs144952836; hg19: chr2-145157274;