Genetic Variant NM_014795.4:c.582A>C (chr2-144404846-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_014795.4(ZEB2):c.582A>C(p.Gln194His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. Q194Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ZEB2
NM_014795.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.413

Publications

0 publications found

Variant links:

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

ZEB2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08758542).

BP6

Variant 2-144404846-T-G is Benign according to our data. Variant chr2-144404846-T-G is described in ClinVar as Benign. ClinVar VariationId is 1660286.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014795.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZEB2	NM_014795.4	MANE Select	c.582A>C	p.Gln194His	missense	Exon 5 of 10	NP_055610.1
	ZEB2	NM_001171653.2		c.510A>C	p.Gln170His	missense	Exon 4 of 9	NP_001165124.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZEB2	ENST00000627532.3	TSL:1 MANE Select	c.582A>C	p.Gln194His	missense	Exon 5 of 10	ENSP00000487174.1
ZEB2	ENST00000558170.6	TSL:1	c.582A>C	p.Gln194His	missense	Exon 4 of 9	ENSP00000454157.1
ZEB2	ENST00000303660.8	TSL:1	c.579A>C	p.Gln193His	missense	Exon 5 of 10	ENSP00000302501.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mowat-Wilson syndrome

Benign:1

Jan 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.0079

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.78

M_CAP

Benign

0.011

MetaRNN

Benign

0.088

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.17

PhyloP100

0.41

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.44

REVEL

Benign

0.20

Sift

Benign

1.0

Sift4G

Benign

0.97

Polyphen

0.0

Vest4

0.35

MutPred

0.22

Loss of loop (P = 0.1258)

MVP

0.41

MPC

0.66

ClinPred

0.11

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.034

gMVP

0.55

Mutation Taster

=70/30

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over