Genetic Variant NM_014795.4:c.1916T>C (chr2-144399271-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014795.4(ZEB2):c.1916T>C(p.Val639Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

ZEB2
NM_014795.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

Publications

0 publications found

Variant links:

COSMIC-nc: COSV57967275

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21730691).

BS2

High AC in GnomAdExome4 at 10 AD gene.

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.1916T>C	p.Val639Ala	missense	Exon 8 of 10	NP_055610.1
	ZEB2	NM_001171653.2		c.1844T>C	p.Val615Ala	missense	Exon 7 of 9	NP_001165124.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZEB2	ENST00000627532.3	TSL:1 MANE Select	c.1916T>C	p.Val639Ala	missense	Exon 8 of 10	ENSP00000487174.1
ZEB2	ENST00000558170.6	TSL:1	c.1916T>C	p.Val639Ala	missense	Exon 7 of 9	ENSP00000454157.1
ZEB2	ENST00000303660.8	TSL:1	c.1913T>C	p.Val638Ala	missense	Exon 8 of 10	ENSP00000302501.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251302

AF XY:

0.00

show subpopulations

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 15, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0076

Eigen

Benign

0.028

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

M_CAP

Benign

0.0072

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

9.3

PrimateAI

Uncertain

0.71

PROVEAN

Benign

0.16

REVEL

Benign

0.24

Sift

Benign

0.66

Sift4G

Benign

0.76

Polyphen

0.55

Vest4

0.46

MutPred

0.33

Loss of stability (P = 0.0304)

MVP

0.19

MPC

0.88

ClinPred

0.31

GERP RS

5.5

Varity_R

0.054

gMVP

0.28

Mutation Taster

=60/40

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over