rs143450927

chr2-144396406-T-Achr2-144396406-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_014795.4(ZEB2):c.3067+6A>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,612,920 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 0.0072 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (273 hom.)
• Consequence: ZEB2 NM_014795.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.003162
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.18

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 2-144396406-T-A is Benign according to our data. Variant chr2-144396406-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 95633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-144396406-T-A is described in Lovd as [Benign]. Variant chr2-144396406-T-A is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZEB2	NM_014795.4	c.3067+6A>T		splice_donor_region_variant, intron_variant		ENST00000627532.3
ZEB2	NM_001171653.2	c.2995+6A>T		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZEB2	ENST00000627532.3	c.3067+6A>T		splice_donor_region_variant, intron_variant		1	NM_014795.4	P4

Frequencies

GnomAD3 genomes AF: 0.00715 AC: 1088 AN: 152232 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0515

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0375

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0173 AC: 4349 AN: 251452 Hom.: 227 AF XY: 0.0132 AC XY: 1789 AN XY: 135902

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0369

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00422 AC: 6160 AN: 1460570 Hom.: 273 Cov.: 32 AF XY: 0.00364 AC XY: 2645 AN XY: 726626

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.0977

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.0312

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.00415

GnomAD4 genome AF: 0.00717 AC: 1092 AN: 152350 Hom.: 41 Cov.: 32 AF XY: 0.00776 AC XY: 578 AN XY: 74500

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.0518

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.0376

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.000855 Hom.: 0

Bravo AF: 0.0140

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 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	Athena Diagnostics	Jul 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jan 30, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	Mar 02, 2015	This variant was interpreted as benign based on ACMG evidence categories BS1 BS2. -

Mowat-Wilson syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 10, 2013	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 09, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	20
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0032
dbscSNV1_RF	Benign	0.070
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: rs143450927; hg19: chr2-145153973;