chr2-144429880-C-T

Variant names:

• chr2-144429880-C-T
• rs767169568
• NM_014795.4:c.220G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_014795.4(ZEB2):​c.220G>A​(p.Val74Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V74V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ZEB2 NM_014795.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.15
• Publications: 1 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11346832).
• BP6: Variant 2-144429880-C-T is Benign according to our data. Variant chr2-144429880-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437331.
• BS2: High AC in GnomAdExome4 at 16 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.220G>A	p.Val74Met	missense	Exon 3 of 10	NP_055610.1	O60315-1
	ZEB2	NM_001171653.2		c.220G>A	p.Val74Met	missense	Exon 3 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.220G>A	p.Val74Met	missense	Exon 3 of 10	ENSP00000487174.1	O60315-1
	ZEB2	ENST00000558170.6	TSL:1	c.220G>A	p.Val74Met	missense	Exon 2 of 9	ENSP00000454157.1	O60315-1
	ZEB2	ENST00000303660.8	TSL:1	c.220G>A	p.Val74Met	missense	Exon 3 of 10	ENSP00000302501.4	A0JP08

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251096 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461640 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727120

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111872

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Mowat-Wilson syndrome (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.19
Sift	Benign	0.23	T
Sift4G	Benign	0.064	T
Polyphen		0.0050	B
Vest4		0.30
MutPred		0.16		Gain of glycosylation at P72 (P = 0.089)
MVP		0.36
MPC		0.74
ClinPred		0.30	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.027
gMVP		0.22
Mutation Taster		=88/12	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: rs767169568; hg19: chr2-145187447; COSMIC: COSV105886198; COSMIC: COSV105886198;