chr2-144429803-G-T

Position:

• chr2-144429803-G-T

Variant summary

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

The NM_014795.4(ZEB2):​c.297C>A​(p.Asn99Lys) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N99D) 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: 3.55

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 (HGNC:):

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=0.1713556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.297C>A	p.Asn99Lys	missense_variant	3/10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.297C>A	p.Asn99Lys	missense_variant	3/9		NP_001165124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.297C>A	p.Asn99Lys	missense_variant	3/10	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	0.14
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.014	T;T;T;T;T;.;T;T;T;T;.;T;.;T;T
Eigen	Benign	-0.017
Eigen_PC	Benign	0.010
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	.;L;.;L;.;L;L;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.29	.;.;.;N;.;N;N;N;.;.;.;.;.;N;.
REVEL	Benign	0.15
Sift	Benign	0.039	.;.;.;D;.;D;D;D;.;.;.;.;.;D;.
Sift4G	Benign	0.78	.;T;T;T;.;T;T;T;T;.;.;T;.;D;.
Polyphen		0.0080	.;B;.;B;.;.;B;B;.;.;.;.;.;.;.
Vest4		0.33, 0.50, 0.29, 0.28, 0.27, 0.35, 0.45
MutPred		0.37		Gain of ubiquitination at N99 (P = 0.006);Gain of ubiquitination at N99 (P = 0.006);Gain of ubiquitination at N99 (P = 0.006);Gain of ubiquitination at N99 (P = 0.006);Gain of ubiquitination at N99 (P = 0.006);Gain of ubiquitination at N99 (P = 0.006);Gain of ubiquitination at N99 (P = 0.006);Gain of ubiquitination at N99 (P = 0.006);.;.;Gain of ubiquitination at N99 (P = 0.006);.;Gain of ubiquitination at N99 (P = 0.006);Gain of ubiquitination at N99 (P = 0.006);Gain of ubiquitination at N99 (P = 0.006);
MVP		0.61
MPC		0.85
ClinPred		0.24	T
GERP RS		3.9
Varity_R		0.047
gMVP		0.097

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: rs147603619; hg19: chr2-145187370;