2-144398860-T-C

Position:

• chr2-144398860-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_014795.4(ZEB2):​c.2327A>G​(p.Asp776Gly) 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 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: 4.97

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ZEB2. . Gene score misZ 3.9433 (greater than the threshold 3.09). Trascript score misZ 5.6227 (greater than threshold 3.09). GenCC has associacion of gene with Mowat-Wilson syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.267129).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.2327A>G	p.Asp776Gly	missense_variant	8/10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.2255A>G	p.Asp752Gly	missense_variant	7/9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.2327A>G	p.Asp776Gly	missense_variant	8/10	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

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 23, 2017	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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C35"). This variant has not been reported in the literature in individuals with ZEB2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glycine at codon 776 of the ZEB2 protein (p.Asp776Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.2327A>Gp.Asp776Gly variant in ZEB2 gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Asp776Gly variant is novel not in any individuals in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid change p.Asp776Gly in ZEB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asp at position 776 is changed to a Gly 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;T;T;T;T;.;T;T;T;T;.;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	.;.;.;.;D;D;D;.;.;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	.;.;.;.;.;.;.;L;L;.;.;L;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.91	.;.;.;.;.;.;.;.;N;.;N;N;.
REVEL	Benign	0.23
Sift	Benign	0.056	.;.;.;.;.;.;.;.;T;.;T;T;.
Sift4G	Benign	0.35	.;.;.;.;.;.;.;T;T;.;T;T;T
Polyphen		0.94	.;.;.;.;.;.;.;P;P;.;.;P;P
Vest4		0.50, 0.47, 0.49, 0.48, 0.49
MutPred		0.099		.;.;.;.;.;.;.;Loss of ubiquitination at K774 (P = 0.0553);Loss of ubiquitination at K774 (P = 0.0553);Loss of ubiquitination at K774 (P = 0.0553);.;Loss of ubiquitination at K774 (P = 0.0553);.;
MVP		0.36
MPC		1.6
ClinPred		0.61	D
GERP RS		5.4
Varity_R		0.25
gMVP		0.42

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: rs1553961558; hg19: chr2-145156427;