rs730881184

Positions:

• chr2-144429961-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Moderate BP6_Very_Strong BS2

The NM_014795.4(ZEB2):​c.139G>T​(p.Ala47Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,634 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 Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.79

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 Benign. Variant got -13 ACMG points.

• 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=0.21674573).
• BP6: Variant 2-144429961-C-A is Benign according to our data. Variant chr2-144429961-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 181722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.139G>T	p.Ala47Ser	missense_variant	3/10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.139G>T	p.Ala47Ser	missense_variant	3/9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.139G>T	p.Ala47Ser	missense_variant	3/10	1	NM_014795.4	ENSP00000487174	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 251016 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135666

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000410 AC: 6 AN: 1461634 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000491

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mowat-Wilson syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2014

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	Benign	0.088
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.0027	T;T;T;T;T;.;T;T;T;T;.;T;.;T;T;.;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;.;D;.;D;D;D;D;D;D;D;D;T;D;D;D;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.18	.;N;.;N;.;N;N;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.20	.;.;.;N;.;N;N;N;.;.;.;.;.;N;.;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.50	.;.;.;T;.;T;T;T;.;.;.;.;.;T;.;T;T
Sift4G	Benign	0.85	.;T;T;T;.;T;T;T;T;.;.;T;.;T;.;.;T
Polyphen		0.0090	.;B;.;B;.;.;B;B;.;.;.;.;.;.;.;.;.
Vest4		0.32, 0.31, 0.40, 0.27, 0.29, 0.32, 0.28
MutPred		0.27		Gain of phosphorylation at A47 (P = 0.021);Gain of phosphorylation at A47 (P = 0.021);Gain of phosphorylation at A47 (P = 0.021);Gain of phosphorylation at A47 (P = 0.021);Gain of phosphorylation at A47 (P = 0.021);Gain of phosphorylation at A47 (P = 0.021);Gain of phosphorylation at A47 (P = 0.021);Gain of phosphorylation at A47 (P = 0.021);.;.;Gain of phosphorylation at A47 (P = 0.021);.;Gain of phosphorylation at A47 (P = 0.021);Gain of phosphorylation at A47 (P = 0.021);Gain of phosphorylation at A47 (P = 0.021);Gain of phosphorylation at A47 (P = 0.021);Gain of phosphorylation at A47 (P = 0.021);
MVP		0.56
MPC		0.65
ClinPred		0.13	T
GERP RS		5.9
Varity_R		0.069
gMVP		0.089

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: rs730881184; hg19: chr2-145187528;