2-144388936-G-GA

Position:

• chr2-144388936-G-GA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_014795.4(ZEB2):​c.*514_*515insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 355,314 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00099 (2 hom., cov: 32)
  • Exomes 𝑓: 0.022 (7 hom.)
• Consequence: ZEB2 NM_014795.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.86

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0223 (4678/209690) while in subpopulation SAS AF= 0.0363 (1423/39228). AF 95% confidence interval is 0.0347. There are 7 homozygotes in gnomad4_exome. There are 2766 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 144 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZEB2	NM_014795.4	c.*514_*515insT		3_prime_UTR_variant	10/10	ENST00000627532.3
ZEB2	NM_001171653.2	c.*514_*515insT		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZEB2	ENST00000627532.3	c.*514_*515insT		3_prime_UTR_variant	10/10	1	NM_014795.4	P4

Frequencies

GnomAD3 genomes AF: 0.000996 AC: 145 AN: 145568 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000454

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000342

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000789

Gnomad SAS AF: 0.0134

Gnomad FIN AF: 0.000555

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.000758

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0223 AC: 4678 AN: 209690 Hom.: 7 Cov.: 0 AF XY: 0.0230 AC XY: 2766 AN XY: 120390

Gnomad4 AFR exome AF: 0.0238

Gnomad4 AMR exome AF: 0.0265

Gnomad4 ASJ exome AF: 0.0166

Gnomad4 EAS exome AF: 0.0232

Gnomad4 SAS exome AF: 0.0363

Gnomad4 FIN exome AF: 0.0161

Gnomad4 NFE exome AF: 0.0180

Gnomad4 OTH exome AF: 0.0201

GnomAD4 genome AF: 0.000989 AC: 144 AN: 145624 Hom.: 2 Cov.: 32 AF XY: 0.00113 AC XY: 80 AN XY: 70658

Gnomad4 AFR AF: 0.000453

Gnomad4 AMR AF: 0.000342

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000791

Gnomad4 SAS AF: 0.0132

Gnomad4 FIN AF: 0.000555

Gnomad4 NFE AF: 0.000758

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mowat-Wilson syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs558553086; hg19: chr2-145146503;