Genetic Variant ZEB2:c.*559_*560dupTT (chr2-144388890-G-GAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014795.4(ZEB2):c.*559_*560dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 330,786 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 0 hom. )

Consequence

ZEB2
NM_014795.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.34

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4 link	c.559_560dupTT		3_prime_UTR_variant	Exon 10 of 10	ENST00000627532.3	NP_055610.1	O60315-1
ZEB2	NM_001171653.2 link	c.559_560dupTT		3_prime_UTR_variant	Exon 9 of 9		NP_001165124.1	O60315-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3 link	c.559_560dupTT		3_prime_UTR_variant	Exon 10 of 10	1	NM_014795.4	ENSP00000487174.1		O60315-1

Frequencies

GnomAD3 genomes

AF:

0.0000848

AC:

AN:

117880

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000187

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000896

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000167

Gnomad MID

AF:

0.00455

Gnomad NFE

AF:

0.0000181

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00445

AC:

221

AN:

49662

AF XY:

0.00409

show subpopulations

Gnomad AFR exome

AF:

0.0106

Gnomad AMR exome

AF:

0.00472

Gnomad ASJ exome

AF:

0.00317

Gnomad EAS exome

AF:

0.00845

Gnomad FIN exome

AF:

0.00187

Gnomad NFE exome

AF:

0.00409

Gnomad OTH exome

AF:

0.00460

GnomAD4 exome

AF:

0.00264

AC:

563

AN:

212906

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

295

AN XY:

123126

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00506

AC:

AN:

4944

American (AMR)

AF:

0.00365

AC:

AN:

16416

Ashkenazi Jewish (ASJ)

AF:

0.00143

AC:

AN:

7672

East Asian (EAS)

AF:

0.00545

AC:

AN:

5870

South Asian (SAS)

AF:

0.00272

AC:

111

AN:

40750

European-Finnish (FIN)

AF:

0.00119

AC:

AN:

14254

Middle Eastern (MID)

AF:

0.00531

AC:

AN:

2070

European-Non Finnish (NFE)

AF:

0.00244

AC:

271

AN:

111268

Other (OTH)

AF:

0.00259

AC:

AN:

9662

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.276

Heterozygous variant carriers

109

163

218

272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000848

AC:

AN:

117880

Hom.:

Cov.:

AF XY:

0.0000893

AC XY:

AN XY:

56000

show subpopulations

African (AFR)

AF:

0.000187

AC:

AN:

32004

American (AMR)

AF:

0.0000896

AC:

AN:

11162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2928

East Asian (EAS)

AF:

0.00

AC:

AN:

4092

South Asian (SAS)

AF:

0.00

AC:

AN:

3942

European-Finnish (FIN)

AF:

0.000167

AC:

AN:

5996

Middle Eastern (MID)

AF:

0.00455

AC:

AN:

220

European-Non Finnish (NFE)

AF:

0.0000181

AC:

AN:

55328

Other (OTH)

AF:

0.00

AC:

AN:

1548

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00197

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr2-144388890-G-GAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over