rs1057522361

Variant names:

• chr2-144403926-C-T
• rs1057522361
• NM_014795.4:c.797G>A
• ZEB2 p.Gly266Glu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_014795.4(ZEB2):​c.797G>A​(p.Gly266Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G266G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 6.01
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33157206).
• BP6: Variant 2-144403926-C-T is Benign according to our data. Variant chr2-144403926-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 385903.

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.797G>A	p.Gly266Glu	missense	Exon 6 of 10	NP_055610.1	O60315-1
	ZEB2	NM_001171653.2		c.725G>A	p.Gly242Glu	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.797G>A	p.Gly266Glu	missense	Exon 6 of 10	ENSP00000487174.1	O60315-1
	ZEB2	ENST00000558170.6	TSL:1	c.797G>A	p.Gly266Glu	missense	Exon 5 of 9	ENSP00000454157.1	O60315-1
	ZEB2	ENST00000303660.8	TSL:1	c.794G>A	p.Gly265Glu	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: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Mowat-Wilson syndrome (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.025	N
PhyloP100		6.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.58
Mutation Taster		=61/39	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057522361;

hg19: chr2-145161493;

COSMIC: COSV57968392;

COSMIC: COSV57968392;