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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014795.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZEB2	NM_014795.4	MANE Select	c.2038_2152dupGCTGTGGGCCTTCCTCAGGAATTTGTGAAGGAATGGTTTGAACAACGAAAAGTCTACCAGTACTCAAATTCCAGGTCCCCATCCCTGGAAAGAAGCTCCAAGCCGTTAGCTCCCA	p.Asn718SerfsTer14	frameshift stop_gained	Exon 8 of 10	NP_055610.1	O60315-1
	ZEB2	NM_001171653.2		c.1966_2080dupGCTGTGGGCCTTCCTCAGGAATTTGTGAAGGAATGGTTTGAACAACGAAAAGTCTACCAGTACTCAAATTCCAGGTCCCCATCCCTGGAAAGAAGCTCCAAGCCGTTAGCTCCCA	p.Asn694SerfsTer14	frameshift stop_gained	Exon 7 of 9	NP_001165124.1	O60315-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZEB2	ENST00000627532.3	TSL:1 MANE Select	c.2038_2152dupGCTGTGGGCCTTCCTCAGGAATTTGTGAAGGAATGGTTTGAACAACGAAAAGTCTACCAGTACTCAAATTCCAGGTCCCCATCCCTGGAAAGAAGCTCCAAGCCGTTAGCTCCCA	p.Asn718SerfsTer14	frameshift stop_gained	Exon 8 of 10	ENSP00000487174.1	O60315-1
	ZEB2	ENST00000558170.6	TSL:1	c.2038_2152dupGCTGTGGGCCTTCCTCAGGAATTTGTGAAGGAATGGTTTGAACAACGAAAAGTCTACCAGTACTCAAATTCCAGGTCCCCATCCCTGGAAAGAAGCTCCAAGCCGTTAGCTCCCA	p.Asn718SerfsTer14	frameshift stop_gained	Exon 7 of 9	ENSP00000454157.1	O60315-1
	ZEB2	ENST00000303660.8	TSL:1	c.2035_2149dupGCTGTGGGCCTTCCTCAGGAATTTGTGAAGGAATGGTTTGAACAACGAAAAGTCTACCAGTACTCAAATTCCAGGTCCCCATCCCTGGAAAGAAGCTCCAAGCCGTTAGCTCCCA	p.Asn717SerfsTer14	frameshift stop_gained	Exon 8 of 10	ENSP00000302501.4	A0JP08

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Mowat-Wilson syndrome (1)

Computational scores

Source: dbNSFP v4.9

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;