2-144404020-C-T

Variant names:

• chr2-144404020-C-T
• rs1553962069
• NM_014795.4:c.703G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014795.4(ZEB2):​c.703G>A​(p.Glu235Lys) variant causes a missense 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.703G>A	p.Glu235Lys	missense_variant	Exon 6 of 10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.631G>A	p.Glu211Lys	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.703G>A	p.Glu235Lys	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: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mowat-Wilson syndrome Uncertain:2

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.703G>A (p.Glu235Lys) variant in ZEB2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu235Lys variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Glu235Lys in ZEB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 235 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

Aug 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 534634). This variant has not been reported in the literature in individuals affected with ZEB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 235 of the ZEB2 protein (p.Glu235Lys). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T;T;T;T;T;T;D;D;D;T;.;D;D;D;D;.;D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	.;.;.;.;D;D;.;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	.;.;.;.;.;.;L;.;L;.;.;L;.;.;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.3	.;.;.;.;.;.;.;.;N;.;N;N;.;.;.;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	.;.;.;.;.;.;.;.;D;.;D;D;.;.;.;.;.
Sift4G	Uncertain	0.0050	.;.;.;.;.;.;D;D;D;.;D;D;D;D;.;.;D
Polyphen		1.0	.;.;.;.;.;.;D;.;D;.;.;D;D;.;.;.;.
Vest4		0.89, 0.79, 0.84, 0.88, 0.82, 0.89, 0.85
MutPred		0.50		.;.;.;.;.;Gain of MoRF binding (P = 0.0177);Gain of MoRF binding (P = 0.0177);.;Gain of MoRF binding (P = 0.0177);Gain of MoRF binding (P = 0.0177);.;Gain of MoRF binding (P = 0.0177);.;.;.;Gain of MoRF binding (P = 0.0177);.;
MVP		0.28
MPC		1.8
ClinPred		0.91	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.58
gMVP		0.72

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: rs1553962069; hg19: chr2-145161587;