Genetic Variant ZEB2:p.Met1? (chr2-144518148-T-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PVS1_SupportingBP6_ModerateBS2

The ENST00000392861.6(ZEB2):c.1A>C(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 136,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0015 ( 0 hom. )

Consequence

ZEB2
ENST00000392861.6 initiator_codon

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.680

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 29 codons. Genomic position: 144517350. Lost 0.061 part of the original CDS.

BP6

Variant 2-144518148-T-G is Benign according to our data. Variant chr2-144518148-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 1694967.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 337 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4 link	c.-69-729A>C	intron_variant	Intron 1 of 9	ENST00000627532.3	NP_055610.1	O60315-1
ZEB2	NM_001171653.2 link	c.-69-729A>C	intron_variant	Intron 1 of 8		NP_001165124.1	O60315-2
ZEB2	NR_033258.2 link	n.182-729A>C	intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3 link	c.-69-729A>C		intron_variant	Intron 1 of 9	1	NM_014795.4	ENSP00000487174.1		O60315-1

Frequencies

GnomAD3 genomes

AF:

0.00262

AC:

337

AN:

128690

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000503

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00133

Gnomad ASJ

AF:

0.00638

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00188

Gnomad FIN

AF:

0.00183

Gnomad MID

AF:

0.0117

Gnomad NFE

AF:

0.00407

Gnomad OTH

AF:

0.00224

GnomAD4 exome

AF:

0.00148

AC:

AN:

8118

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

AN XY:

4568

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000678

Gnomad4 ASJ exome

AF:

0.0192

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00196

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00262

AC:

337

AN:

128744

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

155

AN XY:

60768

show subpopulations

Gnomad4 AFR

AF:

0.000502

Gnomad4 AMR

AF:

0.00132

Gnomad4 ASJ

AF:

0.00638

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00189

Gnomad4 FIN

AF:

0.00183

Gnomad4 NFE

AF:

0.00407

Gnomad4 OTH

AF:

0.00223

Alfa

AF:

0.00539

Hom.:

Bravo

AF:

0.00190

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00519

AC:

Asia WGS

AF:

0.000289

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

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ZEB2: BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.061

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.074

PROVEAN

Benign

-0.61

Sift

Pathogenic

0.0

MVP

0.75

GERP RS

-0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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