chr2-144388936-GAAA-G

Variant names:

• chr2-144388936-GAAA-G
• rs558553086
• NM_014795.4:c.*512_*514delTTT

Variant summary

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

The NM_014795.4(ZEB2):​c.*512_*514delTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000441 in 226,530 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: ZEB2 NM_014795.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.*512_*514delTTT		3_prime_UTR	Exon 10 of 10	NP_055610.1	O60315-1
	ZEB2	NM_001171653.2		c.*512_*514delTTT		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.*512_*514delTTT		3_prime_UTR	Exon 10 of 10	ENSP00000487174.1	O60315-1
	ZEB2	ENST00000636471.1	TSL:5	c.*512_*514delTTT		3_prime_UTR	Exon 10 of 10	ENSP00000490317.1	A0A1B0GV02
	ZEB2	ENST00000409487.7	TSL:5	c.*512_*514delTTT		3_prime_UTR	Exon 10 of 10	ENSP00000386854.2	O60315-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000441 AC: 1 AN: 226530 Hom.: 0 AF XY: 0.00000768 AC XY: 1 AN XY: 130246

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

African (AFR) AF: 0.00 AC: 0 AN: 5322

American (AMR) AF: 0.00 AC: 0 AN: 16534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7806

East Asian (EAS) AF: 0.00 AC: 0 AN: 7110

South Asian (SAS) AF: 0.00 AC: 0 AN: 42742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2350

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 120956

Other (OTH) AF: 0.0000943 AC: 1 AN: 10602

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9

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: rs558553086; hg19: chr2-145146503;