rs786204810
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_014795.4(ZEB2):c.2179_2180del(p.Leu727IlefsTer28) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L727L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
ZEB2
NM_014795.4 frameshift
NM_014795.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.16
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 2-144399006-TAA-T is Pathogenic according to our data. Variant chr2-144399006-TAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 189276.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.2179_2180del | p.Leu727IlefsTer28 | frameshift_variant | 8/10 | ENST00000627532.3 | |
ZEB2 | NM_001171653.2 | c.2107_2108del | p.Leu703IlefsTer28 | frameshift_variant | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ZEB2 | ENST00000627532.3 | c.2179_2180del | p.Leu727IlefsTer28 | frameshift_variant | 8/10 | 1 | NM_014795.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Mowat-Wilson syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics | Mar 02, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 26, 2021 | This variant is also known as c.2178delTT (p.Leu727fs754X) and p.L727fs. This premature translational stop signal has been observed in individual(s) with clinical features of Mowat-Wilson syndrome (PMID: 11592033, 19842203). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu727Ilefs*28) in the ZEB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ZEB2 are known to be pathogenic (PMID: 16053902). ClinVar contains an entry for this variant (Variation ID: 189276). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
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Calibrated prediction
Score
Prediction
Splicing
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at