rs745927130

Variant names:

• chr2-144398565-A-C
• rs745927130
• NM_014795.4:c.2622T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-144398565-A-C
• chr2-144398565-A-G
• chr2-144398565-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014795.4(ZEB2):​c.2622T>G​(p.Asn874Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N874T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.170
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10671744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.2622T>G	p.Asn874Lys	missense_variant	Exon 8 of 10	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.2550T>G	p.Asn850Lys	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.2622T>G	p.Asn874Lys	missense_variant	Exon 8 of 10	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727232

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.1
DANN	Benign	0.94
DEOGEN2	Benign	0.0042	T;T;T;T;T;.;T;T;T;T;.;T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.97	.;.;.;.;D;D;D;.;.;D;D;D;D
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	.;.;.;.;.;.;.;L;L;.;.;L;.
PhyloP100		0.17
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.40	.;.;.;.;.;.;.;.;N;.;N;N;N
REVEL	Benign	0.031
Sift	Benign	0.27	.;.;.;.;.;.;.;.;T;.;T;T;D
Sift4G	Benign	0.82	.;.;.;.;.;.;.;T;T;.;T;T;T
Polyphen		0.0080	.;.;.;.;.;.;.;B;B;.;.;B;B
Vest4		0.50, 0.47, 0.68, 0.46, 0.51
MutPred		0.31		.;.;.;.;.;.;.;Gain of ubiquitination at N874 (P = 0.0069);Gain of ubiquitination at N874 (P = 0.0069);Gain of ubiquitination at N874 (P = 0.0069);.;Gain of ubiquitination at N874 (P = 0.0069);.;
MVP		0.14
MPC		0.81
ClinPred		0.19	T
GERP RS		0.89
PromoterAI		-0.0028	Neutral
Varity_R		0.080
gMVP		0.58
Mutation Taster		=85/15	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: rs745927130; hg19: chr2-145156132;