rs767169568

Positions:

• chr2-144429880-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_014795.4(ZEB2):​c.220G>A​(p.Val74Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.15

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 Likely_benign. Variant got -6 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11346832).
• BP6: Variant 2-144429880-C-T is Benign according to our data. Variant chr2-144429880-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437331.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}. Variant chr2-144429880-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.220G>A	p.Val74Met	missense_variant	3/10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.220G>A	p.Val74Met	missense_variant	3/9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.220G>A	p.Val74Met	missense_variant	3/10	1	NM_014795.4	ENSP00000487174	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251096 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135704

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461640 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727120

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: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mowat-Wilson syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 16, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T;T;T;T;T;.;T;T;T;T;.;T;.;T;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D;.;D;.;D;D;D;D;D;D;D;D;D;D;T;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.0	.;L;.;L;.;L;L;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.28	.;.;.;N;.;N;N;N;.;.;.;.;.;N;.;N
REVEL	Benign	0.19
Sift	Benign	0.23	.;.;.;T;.;T;T;T;.;.;.;.;.;T;.;T
Sift4G	Benign	0.064	.;T;T;T;.;T;T;T;T;.;.;T;.;T;.;.
Polyphen		0.0050	.;B;.;B;.;.;B;B;.;.;.;.;.;.;.;.
Vest4		0.30, 0.26, 0.28, 0.29, 0.29, 0.28
MutPred		0.16		Gain of glycosylation at P72 (P = 0.089);Gain of glycosylation at P72 (P = 0.089);Gain of glycosylation at P72 (P = 0.089);Gain of glycosylation at P72 (P = 0.089);Gain of glycosylation at P72 (P = 0.089);Gain of glycosylation at P72 (P = 0.089);Gain of glycosylation at P72 (P = 0.089);Gain of glycosylation at P72 (P = 0.089);.;.;Gain of glycosylation at P72 (P = 0.089);.;Gain of glycosylation at P72 (P = 0.089);Gain of glycosylation at P72 (P = 0.089);Gain of glycosylation at P72 (P = 0.089);Gain of glycosylation at P72 (P = 0.089);
MVP		0.36
MPC		0.74
ClinPred		0.30	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.027
gMVP		0.22

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: rs767169568; hg19: chr2-145187447; COSMIC: COSV105886198; COSMIC: COSV105886198;