rs137852983

Positions:

• chr2-144389740-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The ENST00000627532.3(ZEB2):​c.3356A>G​(p.Gln1119Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1119H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZEB2 ENST00000627532.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ZEB2. . Gene score misZ 3.9433 (greater than the threshold 3.09). Trascript score misZ 5.6227 (greater than threshold 3.09). GenCC has associacion of gene with Mowat-Wilson syndrome.
• PP5: Variant 2-144389740-T-C is Pathogenic according to our data. Variant chr2-144389740-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 4768.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3480911). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.3356A>G	p.Gln1119Arg	missense_variant	10/10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.3284A>G	p.Gln1095Arg	missense_variant	9/9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.3356A>G	p.Gln1119Arg	missense_variant	10/10	1	NM_014795.4	ENSP00000487174	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459496 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725824

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mowat-Wilson syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0078	T;T;T;T;T;.;T;T;T;.;T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	.;.;.;.;D;D;D;.;.;D;D;D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;.;.;.;.;.;.;N;N;.;N;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.69	.;.;.;.;.;.;.;.;N;N;N;.
REVEL	Benign	0.16
Sift	Uncertain	0.026	.;.;.;.;.;.;.;.;D;D;D;.
Sift4G	Benign	0.46	.;.;.;.;.;.;.;T;T;T;T;T
Polyphen		0.0050	.;.;.;.;.;.;.;B;B;.;B;B
Vest4		0.41, 0.44, 0.53, 0.81, 0.60
MutPred		0.78		.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0212);Gain of MoRF binding (P = 0.0212);.;Gain of MoRF binding (P = 0.0212);.;
MVP		0.64
MPC		1.5
ClinPred		0.57	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs137852983; hg19: chr2-145147307;