Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_014795.4(ZEB2):c.2932G>T(p.Asp978Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D978G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ZEB2
NM_014795.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 5.95

Publications

1 publications found

Variant links:

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

ZEB2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-144396547-C-A is Pathogenic according to our data. Variant chr2-144396547-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 217029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014795.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZEB2	NM_014795.4	MANE Select	c.2932G>T	p.Asp978Tyr	missense	Exon 9 of 10	NP_055610.1
	ZEB2	NM_001171653.2		c.2860G>T	p.Asp954Tyr	missense	Exon 8 of 9	NP_001165124.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZEB2	ENST00000627532.3	TSL:1 MANE Select	c.2932G>T	p.Asp978Tyr	missense	Exon 9 of 10	ENSP00000487174.1
ZEB2	ENST00000558170.6	TSL:1	c.2932G>T	p.Asp978Tyr	missense	Exon 8 of 9	ENSP00000454157.1
ZEB2	ENST00000303660.8	TSL:1	c.2929G>T	p.Asp977Tyr	missense	Exon 9 of 10	ENSP00000302501.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mowat-Wilson syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.61

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

6.0

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.28

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0080

Polyphen

0.59

Vest4

0.92

MutPred

0.32

Gain of phosphorylation at D978 (P = 0.0262)

MVP

0.45

MPC

2.8

ClinPred

1.0

GERP RS

5.9

PromoterAI

-0.074

Neutral

(source)

Varity_R

0.78

gMVP

0.82

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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rs863224942

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over