rs727503784

Positions:

• chr2-144429810-CA-C

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.289delT​(p.Trp97fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. 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:4
• Conservation: PhyloP100: 8.58

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 (HGNC:):

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 2-144429810-CA-C is Pathogenic according to our data. Variant chr2-144429810-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 180207.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.289delT	p.Trp97fs	frameshift_variant	3/10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.289delT	p.Trp97fs	frameshift_variant	3/9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.289delT	p.Trp97fs	frameshift_variant	3/10	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mowat-Wilson syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2014	This mutation is denoted as c.289delT at the cDNA level and p.Trp97GlyfsX11 at the protein level; it is in exon 3 in the ZEB2 gene (NM_014795.3). The normal sequence with the base that is deleted in braces is: ACCCC{T}GGCA. The c.289delT mutation in the ZEB2 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. The c.289delT mutation in the ZEB2 gene causes a frameshift starting with codon Tryptophan 97, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Trp97GlyfsX11. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.289delT mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.289delT as a disease-causing mutation, and its presence is consistent with a diagnosis of Mowat-Wilson syndrome, an autosomal dominant disorder. This variant has been observed de novo with confirmed parentage. The variant is found in INFANT-EPI panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 26, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Mendelics	Nov 09, 2014	- -

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: rs727503784; hg19: chr2-145187377;