Variant 9-120778353-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_012164.4(FBXW2):c.683C>G(p.Ala228Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 31)

Exomes 𝑓: 0.010 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FBXW2
NM_012164.4 missense, splice_region

Scores

Splicing: ADA: 0.9333

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.88

Variant links:

Genes affected

FBXW2 (HGNC:13608): (F-box and WD repeat domain containing 2) F-box proteins are an expanding family of eukaryotic proteins characterized by an approximately 40 amino acid motif, the F box. Some F-box proteins have been shown to be critical for the ubiquitin-mediated degradation of cellular regulatory proteins. In fact, F-box proteins are one of the four subunits of ubiquitin protein ligases, called SCFs. SCF ligases bring ubiquitin conjugating enzymes to substrates that are specifically recruited by the different F-box proteins. Mammalian F-box proteins are classified into three groups based on the presence of either WD-40 repeats, leucine-rich repeats, or the presence or absence of other protein-protein interacting domains. This gene encodes the second identified member of the F-box gene family and contains multiple WD-40 repeats. [provided by RefSeq, Jul 2008]

FBXW2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXW2	NM_012164.4 linkuse as main transcript	c.683C>G	p.Ala228Gly	missense_variant, splice_region_variant	4/8	ENST00000608872.6	NP_036296.2	Q9UKT8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXW2	ENST00000608872.6 linkuse as main transcript	c.683C>G	p.Ala228Gly	missense_variant, splice_region_variant	4/8	1	NM_012164.4	ENSP00000476369.1		Q9UKT8-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

143462

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000201

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000690

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00118

Gnomad SAS

AF:

0.000515

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000610

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0101

AC:

8562

AN:

846286

Hom.:

Cov.:

AF XY:

0.00928

AC XY:

4033

AN XY:

434706

show subpopulations

Gnomad4 AFR exome

AF:

0.0113

Gnomad4 AMR exome

AF:

0.00282

Gnomad4 ASJ exome

AF:

0.0103

Gnomad4 EAS exome

AF:

0.0141

Gnomad4 SAS exome

AF:

0.00187

Gnomad4 FIN exome

AF:

0.0136

Gnomad4 NFE exome

AF:

0.0111

Gnomad4 OTH exome

AF:

0.0126

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000223

AC:

AN:

143574

Hom.:

Cov.:

AF XY:

0.000200

AC XY:

AN XY:

69852

show subpopulations

Gnomad4 AFR

AF:

0.000226

Gnomad4 AMR

AF:

0.0000689

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00118

Gnomad4 SAS

AF:

0.000513

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.0000610

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.683C>G (p.A228G) alteration is located in exon 4 (coding exon 2) of the FBXW2 gene. This alteration results from a C to G substitution at nucleotide position 683, causing the alanine (A) at amino acid position 228 to be replaced by a glycine (G). 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

0.97

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.57

D;D

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.58

N;.

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-2.1

.;N

REVEL

Uncertain

0.37

Sift

Benign

0.60

.;T

Sift4G

Benign

0.067

T;.

Polyphen

1.0

D;.

Vest4

0.62

MutPred

0.55

Gain of disorder (P = 0.0752);.;

MVP

0.71

MPC

0.68

ClinPred

0.97

GERP RS

5.5

Varity_R

0.48

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.93

dbscSNV1_RF

Benign

0.65

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.22

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over