2-144404939-G-A

Variant names:

• chr2-144404939-G-A
• rs138859323
• NM_014795.4:c.489C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_014795.4(ZEB2):​c.489C>T​(p.Ile163Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,614,212 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (50 hom.)
• Consequence: ZEB2 NM_014795.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.747
• Publications: 4 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.05).
• BP6: Variant 2-144404939-G-A is Benign according to our data. Variant chr2-144404939-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.747 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

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.489C>T	p.Ile163Ile	synonymous	Exon 5 of 10	NP_055610.1
	ZEB2	NM_001171653.2		c.417C>T	p.Ile139Ile	synonymous	Exon 4 of 9	NP_001165124.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZEB2	ENST00000627532.3	TSL:1 MANE Select	c.489C>T	p.Ile163Ile	synonymous	Exon 5 of 10	ENSP00000487174.1
	ZEB2	ENST00000558170.6	TSL:1	c.489C>T	p.Ile163Ile	synonymous	Exon 4 of 9	ENSP00000454157.1
	ZEB2	ENST00000303660.8	TSL:1	c.486C>T	p.Ile162Ile	synonymous	Exon 5 of 10	ENSP00000302501.4

Frequencies

GnomAD3 genomes AF: 0.00299 AC: 455 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00372 AC: 934 AN: 251314 AF XY: 0.00412

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00361

Gnomad ASJ exome AF: 0.0192

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00392

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00301 AC: 4406 AN: 1461872 Hom.: 50 Cov.: 31 AF XY: 0.00326 AC XY: 2371 AN XY: 727236

African (AFR) AF: 0.00221 AC: 74 AN: 33480

American (AMR) AF: 0.00387 AC: 173 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 519 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.00402 AC: 347 AN: 86256

European-Finnish (FIN) AF: 0.000880 AC: 47 AN: 53408

Middle Eastern (MID) AF: 0.0560 AC: 323 AN: 5768

European-Non Finnish (NFE) AF: 0.00230 AC: 2563 AN: 1112006

Other (OTH) AF: 0.00588 AC: 355 AN: 60396

GnomAD4 genome AF: 0.00298 AC: 454 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.00294 AC XY: 219 AN XY: 74488

African (AFR) AF: 0.000698 AC: 29 AN: 41572

American (AMR) AF: 0.00536 AC: 82 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4828

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10624

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.00335 AC: 228 AN: 68028

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00448 Hom.: 0

Bravo AF: 0.00311

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00694

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Mowat-Wilson syndrome (4)
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	ZEB2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.5
DANN	Benign	0.88
PhyloP100		0.75
Mutation Taster		=100/0	polymorphism

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: rs138859323; hg19: chr2-145162506; COSMIC: COSV57955598; COSMIC: COSV57955598;