2-144399025-G-C

Variant names:

• chr2-144399025-G-C
• rs1240429329
• NM_014795.4:c.2162C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014795.4(ZEB2):​c.2162C>G​(p.Pro721Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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, single submitter U:1
• Conservation: PhyloP100: 7.77

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23987892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.2162C>G	p.Pro721Arg	missense_variant	Exon 8 of 10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.2090C>G	p.Pro697Arg	missense_variant	Exon 7 of 9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.2162C>G	p.Pro721Arg	missense_variant	Exon 8 of 10	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mowat-Wilson syndrome Uncertain:1

May 13, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with ZEB2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with arginine at codon 721 of the ZEB2 protein (p.Pro721Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.0080	T;T;T;T;T;.;T;T;T;T;.;T;T
Eigen	Benign	-0.0067
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;.;.;.;D;D;D;.;.;D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.;N;N;.;.;N;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.18	.;.;.;.;.;.;.;.;N;.;N;N;.
REVEL	Uncertain	0.30
Sift	Benign	0.069	.;.;.;.;.;.;.;.;T;.;T;T;.
Sift4G	Benign	0.52	.;.;.;.;.;.;.;T;T;.;T;T;T
Polyphen		0.077	.;.;.;.;.;.;.;B;B;.;.;B;B
Vest4		0.31, 0.40, 0.26, 0.36
MutPred		0.24		.;.;.;.;.;.;.;Loss of glycosylation at P721 (P = 0.0076);Loss of glycosylation at P721 (P = 0.0076);Loss of glycosylation at P721 (P = 0.0076);.;Loss of glycosylation at P721 (P = 0.0076);.;
MVP		0.22
MPC		0.74
ClinPred		0.60	D
GERP RS		5.2
Varity_R		0.088
gMVP		0.21

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: rs1240429329; hg19: chr2-145156592;