rs1553961598

Variant names:

• chr2-144399034-T-TTGGGAGCTAACGGCTTGGAGCTTCTTTCCAGGGATGGGGACCTGGAATTTGAGTACTGGTAGACTTTTCGTTGTTCAAACCATTCCTTCACAAATTCCTGAGGAAGGCCCACAGC
• rs1553961598
• NM_014795.4:c.2038_2152dupGCTGTGGGCCTTCCTCAGGAATTTGTGAAGGAATGGTTTGAACAACGAAAAGTCTACCAGTACTCAAATTCCAGGTCCCCATCCCTGGAAAGAAGCTCCAAGCCGTTAGCTCCCA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_014795.4(ZEB2):​c.2038_2152dupGCTGTGGGCCTTCCTCAGGAATTTGTGAAGGAATGGTTTGAACAACGAAAAGTCTACCAGTACTCAAATTCCAGGTCCCCATCCCTGGAAAGAAGCTCCAAGCCGTTAGCTCCCA​(p.Asn718SerfsTer14) variant causes a frameshift, stop gained change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZEB2 NM_014795.4 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.72
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-144399034-T-TTGGGAGCTAACGGCTTGGAGCTTCTTTCCAGGGATGGGGACCTGGAATTTGAGTACTGGTAGACTTTTCGTTGTTCAAACCATTCCTTCACAAATTCCTGAGGAAGGCCCACAGC is Pathogenic according to our data. Variant chr2-144399034-T-TTGGGAGCTAACGGCTTGGAGCTTCTTTCCAGGGATGGGGACCTGGAATTTGAGTACTGGTAGACTTTTCGTTGTTCAAACCATTCCTTCACAAATTCCTGAGGAAGGCCCACAGC is described in ClinVar as Pathogenic. ClinVar VariationId is 466279.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.2038_2152dupGCTGTGGGCCTTCCTCAGGAATTTGTGAAGGAATGGTTTGAACAACGAAAAGTCTACCAGTACTCAAATTCCAGGTCCCCATCCCTGGAAAGAAGCTCCAAGCCGTTAGCTCCCA	p.Asn718SerfsTer14	frameshift_variant, stop_gained	Exon 8 of 10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.1966_2080dupGCTGTGGGCCTTCCTCAGGAATTTGTGAAGGAATGGTTTGAACAACGAAAAGTCTACCAGTACTCAAATTCCAGGTCCCCATCCCTGGAAAGAAGCTCCAAGCCGTTAGCTCCCA	p.Asn694SerfsTer14	frameshift_variant, stop_gained	Exon 7 of 9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.2038_2152dupGCTGTGGGCCTTCCTCAGGAATTTGTGAAGGAATGGTTTGAACAACGAAAAGTCTACCAGTACTCAAATTCCAGGTCCCCATCCCTGGAAAGAAGCTCCAAGCCGTTAGCTCCCA	p.Asn718SerfsTer14	frameshift_variant, stop_gained	Exon 8 of 10	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mowat-Wilson syndrome Pathogenic:1

Feb 15, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

While this particular variant has not been reported in the literature, loss-of-function variants in ZEB2 are known to be pathogenic (PMID: 16053902). For these reasons, this variant has been classified as Pathogenic. This sequence change inserts 115 nucleotides in exon 8 of the ZEB2 mRNA (c.2038_2152dup), causing a frameshift at codon 718. This creates a premature translational stop signal (p.Asn718Serfs*14) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1553961598; hg19: chr2-145156601;