chr2-144398426-G-A

Variant names:

• chr2-144398426-G-A
• rs587784566
• NM_014795.4:c.2761C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014795.4(ZEB2):​c.2761C>T​(p.Arg921*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZEB2 NM_014795.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 3.57
• Publications: 8 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-144398426-G-A is Pathogenic according to our data. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144398426-G-A is described in CliVar as Pathogenic. Clinvar id is 160323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.2761C>T	p.Arg921*	stop_gained	Exon 8 of 10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.2689C>T	p.Arg897*	stop_gained	Exon 7 of 9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.2761C>T	p.Arg921*	stop_gained	Exon 8 of 10	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mowat-Wilson syndrome Pathogenic:6

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 13, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg921*) in the ZEB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ZEB2 are known to be pathogenic (PMID: 16053902). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Mowat-Wilson syndrome (PMID: 16053902, 19215041, 24401652, 24715670, 26809768). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 160323). For these reasons, this variant has been classified as Pathogenic. -

Jan 25, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Arg921Ter variant in ZEB2 was identified by our study in one individual with abnormalities of the corpus callosum. Trio exome analysis showed this variant to be de novo. The p.Arg921Ter variant in ZEB2 has been previously reported in 16 unrelated individuals with Mowat Wilson syndrome (PMID: 17203459, PMID: 33619735, PMID: 33199988, PMID: 32593896, PMID: 24401652, PMID: 26809768, PMID: 24715670, PMID: 19215041, PMID: 16053902, SCV001437886.1, SCV000680438.1). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 6 individuals with confirmed paternity and maternity (PMID: 33619735, PMID: 33199988, PMID: 24401652, PMID: 16053902, SCV001437886.1, SCV000680438.1). This variant has also been reported in ClinVar (Variation ID: 160323) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 921, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the ZEB2 gene is an established disease mechanism in autosomal dominant Mowat Wilson syndrome. In summary, this variant meets criteria to be classified as pathogenic for Mowat Wilson syndrome. ACMG/AMP Criteria applied: PVS1, PS2_VeryStrong, PS4, PM2_Supporting (Richards 2015). -

not provided Pathogenic:3

Nov 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 12, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 16053902, 24401652, 29655203, 32593896, 33619735, 33199988) -

Inborn genetic diseases Pathogenic:1

Jul 19, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R921* pathogenic mutation (also known as c.2761C>T), located in coding exon 7 of the ZEB2 gene, results from a C to T substitution at nucleotide position 2761. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation has been detected (some as de novo occurrences) in several individuals with typical Mowat-Wilson syndrome (MWS) facial gestalt and other various MWS symptoms including microcephaly, seizures, and developmental delay (Zweier C et al. Eur J Med Genet Feb;48:97-111; Pons L et al. Orphanet J Rare Dis, 2014 Jan;9:2). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

See cases Pathogenic:1

Dec 20, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PVS1,PM2,PP5 -

Intellectual disability Pathogenic:1

Sep 10, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		3.6
Vest4		0.96, 0.96, 0.96, 0.96, 0.95
GERP RS		4.9
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587784566; hg19: chr2-145155993; COSMIC: COSV57966620; COSMIC: COSV57966620;