2-144388890-G-GA

Variant names:

• chr2-144388890-G-GA
• rs533637050
• NM_014795.4:c.*560dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_014795.4(ZEB2):​c.*560dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0911 in 298,326 control chromosomes in the GnomAD database, including 125 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (124 hom., cov: 32)
  • Exomes 𝑓: 0.13 (1 hom.)
• Consequence: ZEB2 NM_014795.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.34
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.*560dupT		3_prime_UTR_variant	Exon 10 of 10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.*560dupT		3_prime_UTR_variant	Exon 9 of 9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.*560dupT		3_prime_UTR_variant	Exon 10 of 10	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes AF: 0.0323 AC: 3798 AN: 117624 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.0873

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.00308

Gnomad EAS AF: 0.00831

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.0367

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0267

GnomAD2 exomes AF: 0.185 AC: 9193 AN: 49662 AF XY: 0.190

Gnomad AFR exome AF: 0.257

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.197

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.179

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.129 AC: 23364 AN: 180682 Hom.: 1 Cov.: 0 AF XY: 0.128 AC XY: 13101 AN XY: 102746

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

African (AFR) AF: 0.175 AC: 799 AN: 4554

American (AMR) AF: 0.123 AC: 1857 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 803 AN: 6386

East Asian (EAS) AF: 0.137 AC: 716 AN: 5216

South Asian (SAS) AF: 0.139 AC: 4717 AN: 33880

European-Finnish (FIN) AF: 0.0918 AC: 1152 AN: 12544

Middle Eastern (MID) AF: 0.0546 AC: 107 AN: 1958

European-Non Finnish (NFE) AF: 0.131 AC: 12164 AN: 92794

Other (OTH) AF: 0.127 AC: 1049 AN: 8230

⚠️ 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.

GnomAD4 genome AF: 0.0323 AC: 3804 AN: 117644 Hom.: 124 Cov.: 32 AF XY: 0.0319 AC XY: 1781 AN XY: 55886

African (AFR) AF: 0.0874 AC: 2800 AN: 32042

American (AMR) AF: 0.0180 AC: 200 AN: 11136

Ashkenazi Jewish (ASJ) AF: 0.00308 AC: 9 AN: 2924

East Asian (EAS) AF: 0.00835 AC: 34 AN: 4074

South Asian (SAS) AF: 0.0209 AC: 82 AN: 3924

European-Finnish (FIN) AF: 0.0107 AC: 64 AN: 5960

Middle Eastern (MID) AF: 0.0306 AC: 6 AN: 196

European-Non Finnish (NFE) AF: 0.0103 AC: 568 AN: 55180

Other (OTH) AF: 0.0265 AC: 41 AN: 1548

Alfa AF: 0.0436 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mowat-Wilson syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs533637050; hg19: chr2-145146457;