2-144399761-T-G

Variant names:

• chr2-144399761-T-G
• rs778246270
• NM_014795.4:c.1426A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_014795.4(ZEB2):​c.1426A>C​(p.Met476Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M476T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.89
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19389522).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.1426A>C	p.Met476Leu	missense_variant	Exon 8 of 10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.1354A>C	p.Met452Leu	missense_variant	Exon 7 of 9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.1426A>C	p.Met476Leu	missense_variant	Exon 8 of 10	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250910 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461556 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727076

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.000112 AC: 5 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111876

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mowat-Wilson syndrome Uncertain:1

Aug 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. ClinVar contains an entry for this variant (Variation ID: 534642). This variant has not been reported in the literature in individuals affected with ZEB2-related conditions. This variant is present in population databases (rs778246270, gnomAD 0.01%). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 476 of the ZEB2 protein (p.Met476Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Benign	0.51
DEOGEN2	Benign	0.0029	T;T;T;T;T;.;T;T;T;T;.;T;T;T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	.;.;.;.;D;D;D;.;.;D;D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.4	.;.;.;.;.;.;.;L;L;.;.;L;.;.;.
PhyloP100		5.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.30	.;.;.;.;.;.;.;.;N;.;N;N;.;.;.
REVEL	Benign	0.23
Sift	Benign	1.0	.;.;.;.;.;.;.;.;T;.;T;T;.;.;.
Sift4G	Benign	1.0	.;.;.;.;.;.;.;T;T;.;T;T;T;.;.
Polyphen		0.0010, 0.0	.;.;.;.;.;.;.;B;B;.;.;B;B;.;.
Vest4		0.44, 0.46, 0.46, 0.43, 0.44
MutPred		0.64		.;.;.;.;.;.;.;Gain of methylation at K475 (P = 0.0669);Gain of methylation at K475 (P = 0.0669);Gain of methylation at K475 (P = 0.0669);.;Gain of methylation at K475 (P = 0.0669);.;.;Gain of methylation at K475 (P = 0.0669);
MVP		0.37
MPC		0.66
ClinPred		0.077	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.52
Mutation Taster		=88/12	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: rs778246270; hg19: chr2-145157328;