rs150853991

Positions:

• chr2-144403964-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014795.4(ZEB2):​c.759C>T​(p.Arg253Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.000386 in 1,614,156 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 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: ZEB2 NM_014795.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.49

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-144403964-G-A is Benign according to our data. Variant chr2-144403964-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144403964-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.759C>T	p.Arg253Arg	synonymous_variant	6/10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.687C>T	p.Arg229Arg	synonymous_variant	5/9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.759C>T	p.Arg253Arg	synonymous_variant	6/10	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000314 AC: 79 AN: 251466 Hom.: 0 AF XY: 0.000346 AC XY: 47 AN XY: 135904

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000633

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000393 AC: 575 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.000389 AC XY: 283 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000496

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74448

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000458 Hom.: 0

Bravo AF: 0.000272

EpiCase AF: 0.000927

EpiControl AF: 0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	ZEB2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2016	- -

Mowat-Wilson syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 09, 2023	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

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

Other links and lift over

dbSNP: rs150853991; hg19: chr2-145161531;