chr2-144398646-G-T

Position:

• chr2-144398646-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000627532.3(ZEB2):​c.2541C>A​(p.Asn847Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N847H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZEB2 ENST00000627532.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.45

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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12971938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.2541C>A	p.Asn847Lys	missense_variant	8/10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.2469C>A	p.Asn823Lys	missense_variant	7/9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.2541C>A	p.Asn847Lys	missense_variant	8/10	1	NM_014795.4	ENSP00000487174	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251260 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135812

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461798 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mowat-Wilson syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2018

This sequence change replaces asparagine with lysine at codon 847 of the ZEB2 protein (p.Asn847Lys). The asparagine residue is moderately conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs759097498, ExAC 0.01%). This variant has not been reported in the literature in individuals with ZEB2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.019	T;T;T;T;T;.;T;T;T;T;.;T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	.;.;.;.;D;D;D;.;.;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	.;.;.;.;.;.;.;L;L;.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.83	.;.;.;.;.;.;.;.;N;.;N;N;.
REVEL	Benign	0.084
Sift	Benign	0.089	.;.;.;.;.;.;.;.;T;.;T;T;.
Sift4G	Benign	0.48	.;.;.;.;.;.;.;T;T;.;T;T;T
Polyphen		0.079	.;.;.;.;.;.;.;B;B;.;.;B;B
Vest4		0.49, 0.52, 0.53, 0.51, 0.42
MutPred		0.39		.;.;.;.;.;.;.;Gain of ubiquitination at N847 (P = 0.0031);Gain of ubiquitination at N847 (P = 0.0031);Gain of ubiquitination at N847 (P = 0.0031);.;Gain of ubiquitination at N847 (P = 0.0031);.;
MVP		0.20
MPC		0.83
ClinPred		0.10	T
GERP RS		4.8
Varity_R		0.086
gMVP		0.56

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: rs759097498; hg19: chr2-145156213;