chr2-144400160-G-A

Position:

• chr2-144400160-G-A

Variant summary

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

The ENST00000627532.3(ZEB2):​c.1027C>T​(p.Arg343Ter) 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZEB2 ENST00000627532.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 3.90

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 2-144400160-G-A is Pathogenic according to our data. Variant chr2-144400160-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144400160-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.1027C>T	p.Arg343Ter	stop_gained	8/10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.955C>T	p.Arg319Ter	stop_gained	7/9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.1027C>T	p.Arg343Ter	stop_gained	8/10	1	NM_014795.4	ENSP00000487174	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461596 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727026

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mowat-Wilson syndrome Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 23, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	Jan 01, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	Mar 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change creates a premature translational stop signal (p.Arg343*) 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 individuals with Mowat-Wilson syndrome (PMID: 12784289, 15121779, 19842203, 24715670). ClinVar contains an entry for this variant (Variation ID: 189281). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 01, 2021	Variant summary: ZEB2 c.1027C>T (p.Arg343X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in affected individuals (HGMD). The variant was absent in 251184 control chromosomes (gnomAD). c.1027C>T has been reported in the literature in multiple individuals affected with Mowat-Wilson Syndrome (examples: Wilson_2003, Ishihara_2004, Yamada_2014, Schuster_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed this variant after 2014, and all submissions have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 18, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2021	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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 12784289, 31376723, 15384097, 19842203, 24715670, 25608121, 25899569, 16053902) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2021

The c.1027C>T (p.R343*) alteration, located in exon 8 (coding exon 7) of the ZEB2 gene, consists of a C to T substitution at nucleotide position 1027. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 343. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD), the ZEB2 c.1027C>T alteration was not observed, with coverage at this position. This alteration has been detected in several individuals with symptoms consistent with Mowat Wilson syndrome (Wilson, 2003; Zweier, 2005; Yamada, 2014; Paz, 2015). An 18 year old male reported by Wilson et al. (2003) had intellectual disability, epilepsy, microcephaly, tetralogy of Fallot, hypospadias, and pelvi-ureteric junction obstruction._x000D_ _x000D_ reminder to manually add internal co-seg data to report Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.94, 0.94, 0.96, 0.90, 0.97, 0.83
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs786204815; hg19: chr2-145157727; COSMIC: COSV100356564; COSMIC: COSV100356564;