chr2-144404020-C-T

Variant names:

• chr2-144404020-C-T
• rs1553962069
• NM_014795.4:c.703G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014795.4(ZEB2):​c.703G>A​(p.Glu235Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.91
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.703G>A	p.Glu235Lys	missense	Exon 6 of 10	NP_055610.1	O60315-1
	ZEB2	NM_001171653.2		c.631G>A	p.Glu211Lys	missense	Exon 5 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.703G>A	p.Glu235Lys	missense	Exon 6 of 10	ENSP00000487174.1	O60315-1
	ZEB2	ENST00000558170.6	TSL:1	c.703G>A	p.Glu235Lys	missense	Exon 5 of 9	ENSP00000454157.1	O60315-1
	ZEB2	ENST00000303660.8	TSL:1	c.700G>A	p.Glu234Lys	missense	Exon 6 of 10	ENSP00000302501.4	A0JP08

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Mowat-Wilson syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.50		Gain of MoRF binding (P = 0.0177)
MVP		0.28
MPC		1.8
ClinPred		0.91	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.58
gMVP		0.72
Mutation Taster		=31/69	disease causing

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: rs1553962069; hg19: chr2-145161587;