2-144400257-G-A

Variant names:

• chr2-144400257-G-A
• rs6711223
• NM_014795.4:c.930C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014795.4(ZEB2):​c.930C>T​(p.Tyr310Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,609,982 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (27 hom.)
• Consequence: ZEB2 NM_014795.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.222
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 2-144400257-G-A is Benign according to our data. Variant chr2-144400257-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.222 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0103 (1574/152316) while in subpopulation AFR AF = 0.0314 (1304/41566). AF 95% confidence interval is 0.03. There are 26 homozygotes in GnomAd4. There are 783 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1574 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.930C>T	p.Tyr310Tyr	synonymous	Exon 8 of 10	NP_055610.1
	ZEB2	NM_001171653.2		c.858C>T	p.Tyr286Tyr	synonymous	Exon 7 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.930C>T	p.Tyr310Tyr	synonymous	Exon 8 of 10	ENSP00000487174.1
	ZEB2	ENST00000558170.6	TSL:1	c.930C>T	p.Tyr310Tyr	synonymous	Exon 7 of 9	ENSP00000454157.1
	ZEB2	ENST00000303660.8	TSL:1	c.927C>T	p.Tyr309Tyr	synonymous	Exon 8 of 10	ENSP00000302501.4

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1572 AN: 152198 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00393 AC: 963 AN: 245024 AF XY: 0.00318

Gnomad AFR exome AF: 0.0351

Gnomad AMR exome AF: 0.00650

Gnomad ASJ exome AF: 0.00220

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00119

Gnomad OTH exome AF: 0.00416

GnomAD4 exome AF: 0.00190 AC: 2768 AN: 1457666 Hom.: 27 Cov.: 32 AF XY: 0.00176 AC XY: 1277 AN XY: 725310

African (AFR) AF: 0.0316 AC: 1059 AN: 33464

American (AMR) AF: 0.00640 AC: 286 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26124

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.000557 AC: 48 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49384

Middle Eastern (MID) AF: 0.00920 AC: 53 AN: 5764

European-Non Finnish (NFE) AF: 0.000912 AC: 1014 AN: 1111920

Other (OTH) AF: 0.00422 AC: 255 AN: 60368

GnomAD4 genome AF: 0.0103 AC: 1574 AN: 152316 Hom.: 26 Cov.: 32 AF XY: 0.0105 AC XY: 783 AN XY: 74486

African (AFR) AF: 0.0314 AC: 1304 AN: 41566

American (AMR) AF: 0.0100 AC: 153 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 68026

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.00414 Hom.: 18

Bravo AF: 0.0128

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00154

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Mowat-Wilson syndrome (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.9
DANN	Benign	0.52
PhyloP100		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6711223; hg19: chr2-145157824;