2-144517420-C-T

Variant names:

• chr2-144517420-C-T
• rs587776612
• ENST00000558170.6:c.-70G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_014795.4(ZEB2):​c.-69-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: ZEB2 NM_014795.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 4.26

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.3, offset of 26, new splice context is: cctgcgtgctgccgaagcAGggc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZEB2	NM_014795.4	c.-69-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 9	ENST00000627532.3	NP_055610.1
ZEB2	NM_001171653.2	c.-69-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 8		NP_001165124.1
ZEB2	NR_033258.2	n.182-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZEB2	ENST00000627532.3	c.-69-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 9	1	NM_014795.4	ENSP00000487174.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mowat-Wilson syndrome Pathogenic:1 Uncertain:1

Apr 15, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the ZEB2 gene. It does not change the encoded amino acid sequence of the ZEB2 protein. RNA analysis indicates that this variant induces altered splicing and is likely to result in the loss of the initiator methionine. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Mowat-Wilson syndrome (PMID: 16532472). This variant is also known as c.1-70G>A. ClinVar contains an entry for this variant (Variation ID: 4767). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of 2, and is expected to result in the loss of the initiator methionine (PMID: 16532472). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	34
DANN	Uncertain	0.98
FATHMM_MKL	Uncertain	0.81	D
GERP RS		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.96		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587776612; hg19: chr2-145274987;