NM_014795.4:c.2038_2152dupGCTGTGGGCCTTCCTCAGGAATTTGTGAAGGAATGGTTTGAACAACGAAAAGTCTACCAGTACTCAAATTCCAGGTCCCCATCCCTGGAAAGAAGCTCCAAGCCGTTAGCTCCCA

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 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. 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

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-144399034-T-TTGGGAGCTAACGGCTTGGAGCTTCTTTCCAGGGATGGGGACCTGGAATTTGAGTACTGGTAGACTTTTCGTTGTTCAAACCATTCCTTCACAAATTCCTGAGGAAGGCCCACAGC is Pathogenic according to our data. Variant chr2-144399034-T-TTGGGAGCTAACGGCTTGGAGCTTCTTTCCAGGGATGGGGACCTGGAATTTGAGTACTGGTAGACTTTTCGTTGTTCAAACCATTCCTTCACAAATTCCTGAGGAAGGCCCACAGC is described in ClinVar as [Pathogenic]. Clinvar id 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553961598; hg19: chr2-145156601;