rs1553961332

Variant names:

• chr2-144396456-A-C
• rs1553961332
• NM_014795.4:c.3023T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_014795.4(ZEB2):​c.3023T>G​(p.Phe1008Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.27
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 2-144396456-A-C is Pathogenic according to our data. Variant chr2-144396456-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 547836.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.3023T>G	p.Phe1008Cys	missense_variant	Exon 9 of 10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.2951T>G	p.Phe984Cys	missense_variant	Exon 8 of 9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.3023T>G	p.Phe1008Cys	missense_variant	Exon 9 of 10	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mowat-Wilson syndrome Pathogenic:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T;T;T;T;T;.;T;D;D;T;.;.;D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;.;.;.;D;D;D;.;.;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;.;.;M;M;.;.;.;M;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.5	.;.;.;.;.;.;.;.;.;D;.;.;D;D;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	.;.;.;.;.;.;.;.;.;D;.;.;D;D;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;.;.;D;D;.;.;D;D;D
Polyphen		1.0	.;.;.;.;.;.;.;.;D;D;.;.;.;D;D
Vest4		0.97, 0.96, 0.97, 0.96, 0.96
MutPred		0.87		.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.1084);Loss of MoRF binding (P = 0.1084);Loss of MoRF binding (P = 0.1084);.;.;Loss of MoRF binding (P = 0.1084);.;
MVP		0.66
MPC		2.9
ClinPred		1.0	D
GERP RS		5.9
PromoterAI		-0.033	Neutral
Varity_R		0.87
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1553961332; hg19: chr2-145154023;