Genetic Variant NM_014038.3:c.664G>A (chr7-16694846-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014038.3(BZW2):c.664G>A(p.Val222Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000146 in 1,367,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

BZW2
NM_014038.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.61

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24793899).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BZW2	NM_014038.3 link	c.664G>A	p.Val222Ile	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.664G>A	p.Val222Ile	missense_variant	Exon 8 of 12	1	NM_014038.3	ENSP00000258761.3		Q9Y6E2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1367528

Hom.:

Cov.:

AF XY:

0.00000297

AC XY:

AN XY:

672658

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32146

American (AMR)

AF:

0.00

AC:

AN:

41610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23718

East Asian (EAS)

AF:

0.00

AC:

AN:

38442

South Asian (SAS)

AF:

0.00

AC:

AN:

74596

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5326

European-Non Finnish (NFE)

AF:

0.00000191

AC:

AN:

1046302

Other (OTH)

AF:

0.00

AC:

AN:

55262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.664G>A (p.V222I) alteration is located in exon 8 (coding exon 7) of the BZW2 gene. This alteration results from a G to A substitution at nucleotide position 664, causing the valine (V) at amino acid position 222 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

Benign

0.084

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0042

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

Eigen

Benign

0.075

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

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

M_CAP

Benign

0.020

MetaRNN

Benign

0.25

T;T;T;T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.34

.;N;N;.;.;.;.

PhyloP100

6.6

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.31

N;N;N;N;N;.;N

REVEL

Benign

0.23

Sift

Benign

0.65

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

Sift4G

Benign

0.62

T;T;T;T;T;T;T

Polyphen

0.0040

B;B;B;.;.;.;.

Vest4

0.16, 0.15, 0.14, 0.12

MutPred

0.32

Gain of helix (P = 0.2684);Gain of helix (P = 0.2684);Gain of helix (P = 0.2684);.;Gain of helix (P = 0.2684);.;.;

MVP

0.40

MPC

0.43

ClinPred

0.58

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.050

gMVP

0.12

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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NM_014038.3:c.664G>A

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