rs1057522361

Variant names:

• chr2-144403926-C-T
• rs1057522361
• NM_014795.4:c.797G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_014795.4(ZEB2):​c.797G>A​(p.Gly266Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G266G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 6.01
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Mowat-Wilson syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33157206).
• BP6: Variant 2-144403926-C-T is Benign according to our data. Variant chr2-144403926-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 385903.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.797G>A	p.Gly266Glu	missense_variant	Exon 6 of 10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.725G>A	p.Gly242Glu	missense_variant	Exon 5 of 9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.797G>A	p.Gly266Glu	missense_variant	Exon 6 of 10	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mowat-Wilson syndrome Uncertain:1 Benign:1

Jun 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 266 of the ZEB2 protein (p.Gly266Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ZEB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 385903). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt ZEB2 function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

May 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.797G>A (p.G266E) alteration is located in exon 6 (coding exon 5) of the ZEB2 gene. This alteration results from a G to A substitution at nucleotide position 797, causing the glycine (G) at amino acid position 266 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Nov 01, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	T;T;T;T;T;.;T;D;T;D;T;.;D;T;T;T;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	.;.;.;.;D;D;D;.;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.025	.;.;.;.;.;.;.;N;.;N;.;.;N;.;.;.;.;.
PhyloP100		6.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.7	.;.;.;.;.;.;.;.;.;D;.;D;D;.;.;.;.;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	.;.;.;.;.;.;.;.;.;D;.;D;D;.;.;.;.;.
Sift4G	Uncertain	0.0080	.;.;.;.;.;.;.;D;D;D;.;D;D;D;D;.;.;D
Polyphen		0.96	.;.;.;.;.;.;.;D;.;D;.;.;D;D;.;.;.;.
Vest4		0.45, 0.46, 0.53, 0.45, 0.47, 0.47, 0.44
MutPred		0.40		.;.;.;.;.;.;Gain of ubiquitination at K264 (P = 0.0861);Gain of ubiquitination at K264 (P = 0.0861);.;Gain of ubiquitination at K264 (P = 0.0861);Gain of ubiquitination at K264 (P = 0.0861);.;Gain of ubiquitination at K264 (P = 0.0861);.;.;.;Gain of ubiquitination at K264 (P = 0.0861);.;
MVP		0.11
MPC		1.9
ClinPred		0.75	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.58
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs1057522361; hg19: chr2-145161493; COSMIC: COSV57968392; COSMIC: COSV57968392;