rs587776604

Positions:

• chr2-144399760-A-AT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014795.4(ZEB2):​c.1426_1427insA​(p.Met476AsnfsTer6) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. 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 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.89

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 Pathogenic. Variant got 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 2-144399760-A-AT is Pathogenic according to our data. Variant chr2-144399760-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 4757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.1426_1427insA	p.Met476AsnfsTer6	frameshift_variant	8/10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.1354_1355insA	p.Met452AsnfsTer6	frameshift_variant	7/9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.1426_1427insA	p.Met476AsnfsTer6	frameshift_variant	8/10	1	NM_014795.4	ENSP00000487174	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mowat-Wilson syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 03, 2021	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4757). This variant is also known as 1421insA . This premature translational stop signal has been observed in individual(s) with Mowat-Wilson syndrome (PMID: 11448942, 27831545). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Met476Asnfs*6) 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). -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 25, 2023	The heterozygous p.Met476AsnfsTer6 variant in ZEB2 was identified by our study in one individual with agenesis of the corpus callosum, seizures, and global developmental delay. Trio exome analysis showed this variant to be de novo. The p.Met476AsnfsTer6 variant in ZEB2 has been previously reported in one individual with Mowat Wilson syndrome (PMID: 11448942). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 4757) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 476 and leads to a premature termination codon 6 amino acids downstream. This alteration is then 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_Supporting, PS4_Supporting, PM2_Supporting (Richards 2015). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2018	The c.1426dupA variant in the ZEB2 gene has been reported previously (as 1421 insA in the SIP1 gene due to alternate nomenclature) in an individual with Mowat-Wilson syndrome described as syndromic Hirschsprung disease with intellectual disability, microcephaly, facial dysmorphism and other anomalies (Cacheux et al., 2001; Dastot-Le Moal et al., 2007). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1426dupA variant causes a frameshift starting with codon Methionine 476, changes this amino acid to an Asparagine residue, and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Met476AsnfsX6. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 01, 2017	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2019

The c.1426dupA pathogenic mutation (also referred to as 1421insA), located in coding exon 7 of the ZEB2 gene, results from a duplication of A at nucleotide position 1426, causing a translational frameshift with a predicted alternate stop codon (p.M476Nfs*6). This pathogenic mutation was identified in one patient from a cohort with Hirschsprung disease, intellectual disability, microcephaly, and distinctive facial phenotype (Cacheux V et al. Hum. Mol. Genet., 2001 Jul;10:1503-10). Additional features observed in this individual have been described in other publications, and include: heart defect (pulmonary atresia, ventricular septal defect, dysplastic mitral valve), failure-to-thrive, and seizures (Mowat DR et al. J. Med. Genet., 1998 Aug;35:617-23), broad halluces, submucous cleft, depigmentation, autonomic dysregulation (Dastot-Le Moal F et al. Hum. Mutat., 2007 Apr;28:313-21), and brain MRI findings of partial agenesis of the corpus callosum, ventricular temporal horn enlargement, and hippocampal abnormalities (Garavelli L et al. Genet. Med., 2017 06;19:691-700). 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. -

Computational scores

Source: dbNSFP v4.3

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: rs587776604; hg19: chr2-145157327;