rs1553961598

chr2-144399034-T-TTGGGAGCTAACGGCTTGGAGCTTCTTTCCAGGGATGGGGACCTGGAATTTGAGTACTGGTAGACTTTTCGTTGTTCAAACCATTCCTTCACAAATTCCTGAGGAAGGCCCACAGC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014795.4(ZEB2):c.2152_2153insGCTGTGGGCCTTCCTCAGGAATTTGTGAAGGAATGGTTTGAACAACGAAAAGTCTACCAGTACTCAAATTCCAGGTCCCCATCCCTGGAAAGAAGCTCCAAGCCGTTAGCTCCCA(p.Asn718SerfsTer14) variant causes a stop gained, frameshift 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 stop_gained, frameshift
• 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/exons	MANE	UniProt
ZEB2	NM_014795.4	c.2152_2153insGCTGTGGGCCTTCCTCAGGAATTTGTGAAGGAATGGTTTGAACAACGAAAAGTCTACCAGTACTCAAATTCCAGGTCCCCATCCCTGGAAAGAAGCTCCAAGCCGTTAGCTCCCA	p.Asn718SerfsTer14	stop_gained, frameshift_variant	8/10	ENST00000627532.3
ZEB2	NM_001171653.2	c.2080_2081insGCTGTGGGCCTTCCTCAGGAATTTGTGAAGGAATGGTTTGAACAACGAAAAGTCTACCAGTACTCAAATTCCAGGTCCCCATCCCTGGAAAGAAGCTCCAAGCCGTTAGCTCCCA	p.Asn694SerfsTer14	stop_gained, frameshift_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZEB2	ENST00000627532.3	c.2152_2153insGCTGTGGGCCTTCCTCAGGAATTTGTGAAGGAATGGTTTGAACAACGAAAAGTCTACCAGTACTCAAATTCCAGGTCCCCATCCCTGGAAAGAAGCTCCAAGCCGTTAGCTCCCA	p.Asn718SerfsTer14	stop_gained, frameshift_variant	8/10	1	NM_014795.4	P4

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 15, 2017

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in ZEB2 are known to be pathogenic (PMID: 16053902). 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;