Genetic Variant ZEB2:p.Asn99Lys (chr2-144429803-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014795.4(ZEB2):c.297C>A(p.Asn99Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N99D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

ZEB2
NM_014795.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.55

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1713556).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZEB2	NM_014795.4	MANE Select	c.297C>A	p.Asn99Lys	missense	Exon 3 of 10	NP_055610.1	O60315-1
	ZEB2	NM_001171653.2		c.297C>A	p.Asn99Lys	missense	Exon 3 of 9	NP_001165124.1	O60315-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZEB2	ENST00000627532.3	TSL:1 MANE Select	c.297C>A	p.Asn99Lys	missense	Exon 3 of 10	ENSP00000487174.1	O60315-1
ZEB2	ENST00000558170.6	TSL:1	c.297C>A	p.Asn99Lys	missense	Exon 2 of 9	ENSP00000454157.1	O60315-1
ZEB2	ENST00000303660.8	TSL:1	c.297C>A	p.Asn99Lys	missense	Exon 3 of 10	ENSP00000302501.4	A0JP08

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

250920

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.014

Eigen

Benign

-0.017

Eigen_PC

Benign

0.010

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.015

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.2

PhyloP100

3.6

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.29

REVEL

Benign

0.15

Sift

Benign

0.039

Sift4G

Benign

0.78

Polyphen

0.0080

Vest4

0.33

MutPred

0.37

Gain of ubiquitination at N99 (P = 0.006)

MVP

0.61

MPC

0.85

ClinPred

0.24

GERP RS

3.9

Varity_R

0.047

gMVP

0.097

Mutation Taster

=85/15

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over