rs794727922

Variant names:

• chr2-144398546-T-G
• rs794727922
• NM_014795.4:c.2641A>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_014795.4(ZEB2):​c.2641A>C​(p.Asn881His) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,834 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.27
• Publications: 0 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25388873).
• BP6: Variant 2-144398546-T-G is Benign according to our data. Variant chr2-144398546-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198861.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.2641A>C	p.Asn881His	missense_variant	Exon 8 of 10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.2569A>C	p.Asn857His	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.2641A>C	p.Asn881His	missense_variant	Exon 8 of 10	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

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

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Mar 25, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T;T;T;T;T;.;T;T;T;T;.;T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	.;.;.;.;D;D;D;.;.;D;D;D;D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;.;.;.;.;.;.;L;L;.;.;L;.
PhyloP100		6.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.1	.;.;.;.;.;.;.;.;N;.;N;N;.
REVEL	Benign	0.095
Sift	Benign	0.099	.;.;.;.;.;.;.;.;T;.;T;T;.
Sift4G	Benign	0.16	.;.;.;.;.;.;.;T;T;.;T;T;T
Polyphen		0.94	.;.;.;.;.;.;.;P;P;.;.;P;P
Vest4		0.58, 0.36, 0.61, 0.37, 0.48
MutPred		0.16		.;.;.;.;.;.;.;Gain of catalytic residue at N881 (P = 0.077);Gain of catalytic residue at N881 (P = 0.077);Gain of catalytic residue at N881 (P = 0.077);.;Gain of catalytic residue at N881 (P = 0.077);.;
MVP		0.25
MPC		0.91
ClinPred		0.64	D
GERP RS		6.0
PromoterAI		-0.0058	Neutral
Varity_R		0.16
gMVP		0.46
Mutation Taster		=86/14	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

Other links and lift over

dbSNP: rs794727922; hg19: chr2-145156113;