NM_014795.4:c.3566_3567dupCC

Variant names:

• chr2-144389528-T-TGG
• rs587776609
• NM_014795.4:c.3566_3567dupCC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_014795.4(ZEB2):​c.3566_3567dupCC​(p.Met1190ProfsTer52) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZEB2 NM_014795.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.60
• Publications: 1 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0214 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-144389528-T-TGG is Pathogenic according to our data. Variant chr2-144389528-T-TGG is described in ClinVar as Pathogenic. ClinVar VariationId is 4763.Status of the report is no_assertion_criteria_provided, 0 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.3566_3567dupCC	p.Met1190ProfsTer52	frameshift	Exon 10 of 10	NP_055610.1	O60315-1
	ZEB2	NM_001171653.2		c.3494_3495dupCC	p.Met1166ProfsTer52	frameshift	Exon 9 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.3566_3567dupCC	p.Met1190ProfsTer52	frameshift	Exon 10 of 10	ENSP00000487174.1	O60315-1
	ZEB2	ENST00000558170.6	TSL:1	c.3566_3567dupCC	p.Met1190ProfsTer52	frameshift	Exon 9 of 9	ENSP00000454157.1	O60315-1
	ZEB2	ENST00000303660.8	TSL:1	c.3563_3564dupCC	p.Met1189ProfsTer52	frameshift	Exon 10 of 10	ENSP00000302501.4	A0JP08

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587776609; hg19: chr2-145147095;