2-144388936-GAAA-GAAAA

Variant names:

• chr2-144388936-G-GA
• rs558553086
• NM_014795.4:c.*514dupT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014795.4(ZEB2):​c.*514dupT 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
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 144 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014795.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZEB2	NM_014795.4	MANE Select	c.*514dupT		3_prime_UTR	Exon 10 of 10	NP_055610.1	O60315-1
	ZEB2	NM_001171653.2		c.*514dupT		3_prime_UTR	Exon 9 of 9	NP_001165124.1	O60315-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZEB2	ENST00000627532.3	TSL:1 MANE Select	c.*514dupT		3_prime_UTR	Exon 10 of 10	ENSP00000487174.1	O60315-1
	ZEB2	ENST00000636471.1	TSL:5	c.*514dupT		3_prime_UTR	Exon 10 of 10	ENSP00000490317.1	A0A1B0GV02
	ZEB2	ENST00000409487.7	TSL:5	c.*514dupT		3_prime_UTR	Exon 10 of 10	ENSP00000386854.2	O60315-1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0238 AC: 119 AN: 5002

American (AMR) AF: 0.0265 AC: 413 AN: 15562

Ashkenazi Jewish (ASJ) AF: 0.0166 AC: 121 AN: 7268

East Asian (EAS) AF: 0.0232 AC: 153 AN: 6598

South Asian (SAS) AF: 0.0363 AC: 1423 AN: 39228

European-Finnish (FIN) AF: 0.0161 AC: 198 AN: 12328

Middle Eastern (MID) AF: 0.0173 AC: 40 AN: 2306

European-Non Finnish (NFE) AF: 0.0180 AC: 2012 AN: 111494

Other (OTH) AF: 0.0201 AC: 199 AN: 9904

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.000453 AC: 18 AN: 39730

American (AMR) AF: 0.000342 AC: 5 AN: 14622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3428

East Asian (EAS) AF: 0.000791 AC: 4 AN: 5056

South Asian (SAS) AF: 0.0132 AC: 61 AN: 4622

European-Finnish (FIN) AF: 0.000555 AC: 5 AN: 9010

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.000758 AC: 50 AN: 65978

Other (OTH) AF: 0.00 AC: 0 AN: 2000

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Mowat-Wilson syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs558553086; hg19: chr2-145146503; COSMIC: COSV57965042; COSMIC: COSV57965042;