Genetic Variant BZW2:p.Asn223Ile (chr7-16694850-A-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_014038.3(BZW2):c.668A>T(p.Asn223Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000511 in 1,370,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000051 ( 0 hom. )

Consequence

BZW2
NM_014038.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.25

Publications

0 publications found

Variant links:

Genes affected

BZW2 (HGNC:18808): (basic leucine zipper and W2 domains 2) Enables cadherin binding activity. Predicted to be involved in cell differentiation and nervous system development. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

BZW2 links:

ENSG00000235837 (HGNC:):

ENSG00000235837 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.829

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BZW2	NM_014038.3 link	c.668A>T	p.Asn223Ile	missense_variant	Exon 8 of 12	ENST00000258761.8	NP_054757.1	Q9Y6E2-1A0A024RA42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BZW2	ENST00000258761.8 link	c.668A>T	p.Asn223Ile	missense_variant	Exon 8 of 12	1	NM_014038.3	ENSP00000258761.3		Q9Y6E2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000511

AC:

AN:

1370418

Hom.:

Cov.:

AF XY:

0.00000741

AC XY:

AN XY:

674340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32196

American (AMR)

AF:

0.00

AC:

AN:

41816

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23806

East Asian (EAS)

AF:

0.00

AC:

AN:

38488

South Asian (SAS)

AF:

0.00

AC:

AN:

75200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5336

European-Non Finnish (NFE)

AF:

0.00000668

AC:

AN:

1047952

Other (OTH)

AF:

0.00

AC:

AN:

55404

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 10, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.668A>T (p.N223I) alteration is located in exon 8 (coding exon 7) of the BZW2 gene. This alteration results from a A to T substitution at nucleotide position 668, causing the asparagine (N) at amino acid position 223 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T;T;T;T;.;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;.;D;D;D;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.4

.;M;M;.;.;.;.

PhyloP100

9.2

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-6.7

D;D;D;D;D;.;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0010

D;D;D;D;D;.;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D

Polyphen

1.0

D;D;D;.;.;.;.

Vest4

0.87, 0.86, 0.86, 0.90, 0.84

MutPred

0.50

Loss of relative solvent accessibility (P = 0.107);Loss of relative solvent accessibility (P = 0.107);Loss of relative solvent accessibility (P = 0.107);.;Loss of relative solvent accessibility (P = 0.107);.;.;

MVP

0.64

MPC

1.5

ClinPred

0.99

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.82

Mutation Taster

=9/91

disease causing

(source)

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

Publications

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chr7-16694850-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over