2-144389415-GA-GAA

Variant names:

• chr2-144389415-G-GA
• rs567229506
• NM_014795.4:c.*35dupT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_014795.4(ZEB2):​c.*35dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000374 in 1,574,642 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: ZEB2 NM_014795.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.27
• 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 -6 ACMG points.

• BP6: Variant 2-144389415-G-GA is Benign according to our data. Variant chr2-144389415-G-GA is described in ClinVar as Likely_benign. ClinVar VariationId is 331297.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 17 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.*35dupT		3_prime_UTR	Exon 10 of 10	NP_055610.1	O60315-1
	ZEB2	NM_001171653.2		c.*35dupT		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.*35dupT		3_prime_UTR	Exon 10 of 10	ENSP00000487174.1	O60315-1
	ZEB2	ENST00000558170.6	TSL:1	c.*35dupT		3_prime_UTR	Exon 9 of 9	ENSP00000454157.1	O60315-1
	ZEB2	ENST00000303660.8	TSL:1	c.*35dupT		3_prime_UTR	Exon 10 of 10	ENSP00000302501.4	A0JP08

Frequencies

GnomAD3 genomes AF: 0.000113 AC: 17 AN: 150060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000584

Gnomad SAS AF: 0.000421

Gnomad FIN AF: 0.0000996

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000593

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000264 AC: 61 AN: 231308 AF XY: 0.000216

Gnomad AFR exome AF: 0.000197

Gnomad AMR exome AF: 0.0000312

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00140

Gnomad FIN exome AF: 0.000160

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000402 AC: 572 AN: 1424466 Hom.: 0 Cov.: 30 AF XY: 0.000365 AC XY: 259 AN XY: 710192

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

African (AFR) AF: 0.000153 AC: 5 AN: 32734

American (AMR) AF: 0.0000225 AC: 1 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.0000388 AC: 1 AN: 25780

East Asian (EAS) AF: 0.00180 AC: 71 AN: 39464

South Asian (SAS) AF: 0.000340 AC: 29 AN: 85352

European-Finnish (FIN) AF: 0.000285 AC: 15 AN: 52580

Middle Eastern (MID) AF: 0.000526 AC: 3 AN: 5706

European-Non Finnish (NFE) AF: 0.000397 AC: 428 AN: 1079188

Other (OTH) AF: 0.000321 AC: 19 AN: 59160

⚠️ 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: 0.000113 AC: 17 AN: 150176 Hom.: 0 Cov.: 32 AF XY: 0.000164 AC XY: 12 AN XY: 73222

African (AFR) AF: 0.000171 AC: 7 AN: 40968

American (AMR) AF: 0.00 AC: 0 AN: 15126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.000586 AC: 3 AN: 5122

South Asian (SAS) AF: 0.000421 AC: 2 AN: 4752

European-Finnish (FIN) AF: 0.0000996 AC: 1 AN: 10044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000593 AC: 4 AN: 67414

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000651 Hom.: 0

Bravo AF: 0.000144

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Mowat-Wilson syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs567229506; hg19: chr2-145146982; COSMIC: COSV107331360; COSMIC: COSV107331360;