chr2-144396406-T-A

Variant names:

• chr2-144396406-T-A
• rs143450927
• NM_014795.4:c.3067+6A>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_014795.4(ZEB2):​c.3067+6A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,612,920 control chromosomes in the GnomAD database, including 314 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (273 hom.)
• Consequence: ZEB2 NM_014795.4 splice_region, intron
• Scores: Splicing: ADA: 0.003162
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.18
• Publications: 5 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 2-144396406-T-A is Benign according to our data. Variant chr2-144396406-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0953 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.3067+6A>T		splice_region intron	N/A	NP_055610.1	O60315-1
	ZEB2	NM_001171653.2		c.2995+6A>T		splice_region intron	N/A	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.3067+6A>T		splice_region intron	N/A	ENSP00000487174.1	O60315-1
	ZEB2	ENST00000558170.6	TSL:1	c.3067+6A>T		splice_region intron	N/A	ENSP00000454157.1	O60315-1
	ZEB2	ENST00000303660.8	TSL:1	c.3064+6A>T		splice_region intron	N/A	ENSP00000302501.4	A0JP08

Frequencies

GnomAD3 genomes AF: 0.00715 AC: 1088 AN: 152232 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0515

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0375

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.0173 AC: 4349 AN: 251452 AF XY: 0.0132

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0369

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00422 AC: 6160 AN: 1460570 Hom.: 273 Cov.: 32 AF XY: 0.00364 AC XY: 2645 AN XY: 726626

African (AFR) AF: 0.000628 AC: 21 AN: 33446

American (AMR) AF: 0.0977 AC: 4370 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26126

East Asian (EAS) AF: 0.0312 AC: 1240 AN: 39694

South Asian (SAS) AF: 0.00126 AC: 109 AN: 86198

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53416

Middle Eastern (MID) AF: 0.000839 AC: 4 AN: 4768

European-Non Finnish (NFE) AF: 0.000106 AC: 118 AN: 1111930

Other (OTH) AF: 0.00415 AC: 250 AN: 60276

GnomAD4 genome AF: 0.00717 AC: 1092 AN: 152350 Hom.: 41 Cov.: 32 AF XY: 0.00776 AC XY: 578 AN XY: 74500

African (AFR) AF: 0.00161 AC: 67 AN: 41586

American (AMR) AF: 0.0518 AC: 792 AN: 15304

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

East Asian (EAS) AF: 0.0376 AC: 195 AN: 5192

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68022

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.000855 Hom.: 0

Bravo AF: 0.0140

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Mowat-Wilson syndrome (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.88
PhyloP100		1.2
PromoterAI		0.057	Neutral
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0032
dbscSNV1_RF	Benign	0.070
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: rs143450927; hg19: chr2-145153973;