chr2-144399231-G-T

Position:

• chr2-144399231-G-T

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.1956C>A​(p.Tyr652Ter) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.92

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 2-144399231-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/exons	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.1956C>A	p.Tyr652Ter	stop_gained	8/10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.1884C>A	p.Tyr628Ter	stop_gained	7/9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.1956C>A	p.Tyr652Ter	stop_gained	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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mowat-Wilson syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2016

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
MutationTaster	Benign	1.0	A;A;A;A
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

Other links and lift over

dbSNP: rs587784563; hg19: chr2-145156798;