chr2-144389739-C-G

Position:

• chr2-144389739-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_014795.4(ZEB2):​c.3357G>C​(p.Gln1119His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50

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 1 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=0.239997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.3357G>C	p.Gln1119His	missense_variant	10/10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.3285G>C	p.Gln1095His	missense_variant	9/9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.3357G>C	p.Gln1119His	missense_variant	10/10	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74310

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000313 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mowat-Wilson syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2022

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. This variant disrupts the p.Gln1119 amino acid residue in ZEB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16688751). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 534639). This variant has not been reported in the literature in individuals affected with ZEB2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1119 of the ZEB2 protein (p.Gln1119His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T;T;T;T;T;.;T;T;T;.;T;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	.;.;.;.;D;D;D;.;.;D;D;D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	.;.;.;.;.;.;.;N;N;.;N;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.83	.;.;.;.;.;.;.;.;N;N;N;.
REVEL	Benign	0.11
Sift	Uncertain	0.0070	.;.;.;.;.;.;.;.;D;D;D;.
Sift4G	Benign	0.13	.;.;.;.;.;.;.;T;T;T;T;T
Polyphen		0.88	.;.;.;.;.;.;.;P;P;.;P;P
Vest4		0.39, 0.37, 0.47, 0.54, 0.54
MutPred		0.36		.;.;.;.;.;.;.;Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);.;Gain of helix (P = 0.0117);.;
MVP		0.20
MPC		1.8
ClinPred		0.70	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.69

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: rs1332911302; hg19: chr2-145147306;