chr2-144404939-G-C

Variant names:

• chr2-144404939-G-C
• rs138859323
• NM_014795.4:c.489C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014795.4(ZEB2):​c.489C>G​(p.Ile163Met) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I163I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.747
• Publications: 4 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36863783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.489C>G	p.Ile163Met	missense_variant	Exon 5 of 10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.417C>G	p.Ile139Met	missense_variant	Exon 4 of 9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.489C>G	p.Ile163Met	missense_variant	Exon 5 of 10	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T;T;T;T;T;T;T;T;T;.;T;T;T;T;.;T;.
Eigen	Benign	0.016
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.94	.;.;.;.;D;D;.;.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	.;.;.;.;.;.;M;M;.;.;M;.;.;.;.;.;.
PhyloP100		0.75
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.4	.;.;.;.;.;.;.;N;.;N;N;.;.;.;.;.;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	.;.;.;.;.;.;.;D;.;D;D;.;.;.;.;.;.
Sift4G	Uncertain	0.011	.;.;.;.;.;.;D;D;.;D;D;D;D;.;.;D;.
Polyphen		0.67	.;.;.;.;.;.;P;P;.;.;P;P;.;.;.;.;.
Vest4		0.76, 0.79, 0.79, 0.78, 0.76, 0.56
MutPred		0.26		.;.;.;.;.;Gain of disorder (P = 0.0515);Gain of disorder (P = 0.0515);Gain of disorder (P = 0.0515);Gain of disorder (P = 0.0515);.;Gain of disorder (P = 0.0515);.;.;.;Gain of disorder (P = 0.0515);.;.;
MVP		0.75
MPC		1.7
ClinPred		0.81	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.67
Mutation Taster		=75/25	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: rs138859323; hg19: chr2-145162506;