Genetic Variant ZEB2:c.-488T>C (chr2-144520357-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The ENST00000629520.2(ZEB2):c.-75T>C variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0315 in 448,052 control chromosomes in the GnomAD database, including 314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.028 ( 102 hom., cov: 31)

Exomes 𝑓: 0.033 ( 212 hom. )

Consequence

ZEB2
ENST00000629520.2 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.38

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 links:

ZEB2-AS1 (HGNC:37149): (ZEB2 antisense RNA 1) This gene produces a spliced long non-coding RNA which is a natural antisense transcript corresponding to the 5' UTR of zinc finger E-box binding homeobox 2 (ZEB2). It is thought that this transcript may be involved in the regulation of ZEB2 expression, and may play a role in the progression of bladder cancer. [provided by RefSeq, Aug 2015]

ZEB2-AS1 links:

ENSG00000273537 (HGNC:):

ENSG00000273537 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 2-144520357-A-G is Benign according to our data. Variant chr2-144520357-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 331305.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.028 (4263/152020) while in subpopulation NFE AF= 0.0397 (2700/67968). AF 95% confidence interval is 0.0385. There are 102 homozygotes in gnomad4. There are 2082 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4263 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ZEB2-AS1	NR_040248.2 link	n.284+72A>G	intron_variant	Intron 3 of 3
ZEB2	NM_014795.4 link	c.-488T>C	upstream_gene_variant		ENST00000627532.3	NP_055610.1	O60315-1
ZEB2	NM_001171653.2 link	c.-488T>C	upstream_gene_variant			NP_001165124.1	O60315-2
ZEB2	NR_033258.2 link	n.-238T>C	upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3 link	c.-488T>C		upstream_gene_variant		1	NM_014795.4	ENSP00000487174.1		O60315-1

Frequencies

GnomAD3 genomes

AF:

0.0281

AC:

4265

AN:

151904

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00711

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0231

Gnomad ASJ

AF:

0.0945

Gnomad EAS

AF:

0.000774

Gnomad SAS

AF:

0.0191

Gnomad FIN

AF:

0.0369

Gnomad MID

AF:

0.0350

Gnomad NFE

AF:

0.0397

Gnomad OTH

AF:

0.0278

GnomAD3 exomes

AF:

0.0322

AC:

4263

AN:

132270

Hom.:

106

AF XY:

0.0325

AC XY:

2335

AN XY:

71952

show subpopulations

Gnomad AFR exome

AF:

0.00680

Gnomad AMR exome

AF:

0.0183

Gnomad ASJ exome

AF:

0.102

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0218

Gnomad FIN exome

AF:

0.0331

Gnomad NFE exome

AF:

0.0407

Gnomad OTH exome

AF:

0.0385

GnomAD4 exome

AF:

0.0333

AC:

9865

AN:

296032

Hom.:

212

Cov.:

AF XY:

0.0323

AC XY:

5449

AN XY:

168594

show subpopulations

Gnomad4 AFR exome

AF:

0.00799

Gnomad4 AMR exome

AF:

0.0184

Gnomad4 ASJ exome

AF:

0.0969

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0204

Gnomad4 FIN exome

AF:

0.0306

Gnomad4 NFE exome

AF:

0.0397

Gnomad4 OTH exome

AF:

0.0364

GnomAD4 genome

AF:

0.0280

AC:

4263

AN:

152020

Hom.:

102

Cov.:

AF XY:

0.0280

AC XY:

2082

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.00709

Gnomad4 AMR

AF:

0.0231

Gnomad4 ASJ

AF:

0.0945

Gnomad4 EAS

AF:

0.000776

Gnomad4 SAS

AF:

0.0193

Gnomad4 FIN

AF:

0.0369

Gnomad4 NFE

AF:

0.0397

Gnomad4 OTH

AF:

0.0266

Alfa

AF:

0.0437

Hom.:

Bravo

AF:

0.0265

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 17, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over