2-144399231-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_014795.4(ZEB2):​c.1956C>A​(p.Tyr652*) variant causes a stop gained change. 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

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.92
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]

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ACMG classification

Classification made for transcript

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 2-144399231-G-T is Pathogenic according to our data. Variant chr2-144399231-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 589324.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
ZEB2NM_014795.4 linkc.1956C>A p.Tyr652* stop_gained Exon 8 of 10 ENST00000627532.3 NP_055610.1 O60315-1
ZEB2NM_001171653.2 linkc.1884C>A p.Tyr628* stop_gained Exon 7 of 9 NP_001165124.1 O60315-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZEB2ENST00000627532.3 linkc.1956C>A p.Tyr652* stop_gained Exon 8 of 10 1 NM_014795.4 ENSP00000487174.1 O60315-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Mowat-Wilson syndrome Pathogenic:2
Nov 07, 2021
Genome-Nilou Lab
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

- -

Inborn genetic diseases Pathogenic:1
Jul 08, 2016
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Y652* pathogenic mutation (also known as c.1956C>A), located in coding exon 7 of the ZEB2 gene, results from a C to A substitution at nucleotide position 1956. This changes the amino acid from a tyrosine to a stop codon within coding exon 7. This mutation has been described in a 35-week stillborn male fetus with features consistent with Mowat-Wilson syndrome, including dysmorphic facial features, hypospadias, ventricular septal defect, short corpus callosum, and Hirschsprung disease (Spaggiari E et al. Eur J Med Genet, 2013 Jun;56:297-300). A different nucleotide substitution at the same nucleotide position (c.1956C>G), also resulting in the p.Y652* nonsense mutation, was described in a 19-year-old Indonesian male with Mowat-Wilson syndrome, whose features included severe intellectual disability, hypotonia, onset of seizures at age 2 years, repetitive hand movements, and facial dysmorphism (Mundhofir FE et al. Case Rep Genet, 2012 Dec;2012:949507). 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

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
36
DANN
Uncertain
1.0
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Uncertain
0.92
D
Vest4
0.96, 0.94, 0.95, 0.97, 0.95
GERP RS
5.5

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.

Other links and lift over

dbSNP: rs587784563; hg19: chr2-145156798; API