rs144154908

Variant names:

• chr2-144398984-G-A
• rs144154908
• NM_014795.4:c.2203C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014795.4(ZEB2):​c.2203C>T​(p.Pro735Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,614,204 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P735L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00077 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (31 hom.)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.90
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004328251).
• BP6: Variant 2-144398984-G-A is Benign according to our data. Variant chr2-144398984-G-A is described in ClinVar as Benign. ClinVar VariationId is 95629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000768 (117/152326) while in subpopulation SAS AF = 0.0241 (116/4820). AF 95% confidence interval is 0.0205. There are 2 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 117 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.2203C>T	p.Pro735Ser	missense	Exon 8 of 10	NP_055610.1	O60315-1
	ZEB2	NM_001171653.2		c.2131C>T	p.Pro711Ser	missense	Exon 7 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.2203C>T	p.Pro735Ser	missense	Exon 8 of 10	ENSP00000487174.1	O60315-1
	ZEB2	ENST00000558170.6	TSL:1	c.2203C>T	p.Pro735Ser	missense	Exon 7 of 9	ENSP00000454157.1	O60315-1
	ZEB2	ENST00000303660.8	TSL:1	c.2200C>T	p.Pro734Ser	missense	Exon 8 of 10	ENSP00000302501.4	A0JP08

Frequencies

GnomAD3 genomes AF: 0.000775 AC: 118 AN: 152208 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0243

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00242 AC: 609 AN: 251324 AF XY: 0.00317

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00122 AC: 1782 AN: 1461878 Hom.: 31 Cov.: 32 AF XY: 0.00172 AC XY: 1251 AN XY: 727240

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0195 AC: 1679 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1112004

Other (OTH) AF: 0.00137 AC: 83 AN: 60394

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152326 Hom.: 2 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0241 AC: 116 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.00269 AC: 327

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.48
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.0016
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N
PhyloP100		4.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.070
Sift	Benign	0.53	T
Sift4G	Benign	0.83	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.099		Gain of phosphorylation at P735 (P = 0.014)
MVP		0.10
MPC		0.71
ClinPred		0.0095	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.34
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: rs144154908; hg19: chr2-145156551; COSMIC: COSV57954006; COSMIC: COSV57954006;