Genetic Variant NM_016378.3:c.283G>C (chrX-8170169-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016378.3(VCX2):c.283G>C(p.Val95Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 8)

Exomes 𝑓: 0.000014 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

VCX2
NM_016378.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.548

Variant links:

Genes affected

VCX2 (HGNC:18158): (variable charge X-linked 2) This gene belongs to the VCX/Y gene family, which has multiple members on both X and Y chromosomes that are expressed exclusively in male germ cells. The VCX gene cluster is polymorphic in terms of copy number; different individuals may have a different number of VCX genes. This gene contains two copies of a 30 nt tandem repeat. Deletion of a nearby member of this family was implicated in cognitive disability. [provided by RefSeq, Feb 2015]

VCX2 links:

ENSG00000285679 (HGNC:):

ENSG00000285679 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.055738777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCX2	NM_016378.3 link	c.283G>C	p.Val95Leu	missense_variant	Exon 3 of 3	ENST00000317103.5	NP_057462.2	Q9H322

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VCX2	ENST00000317103.5 link	c.283G>C	p.Val95Leu	missense_variant	Exon 3 of 3	1	NM_016378.3	ENSP00000321309.4	Q9H322
ENSG00000285679	ENST00000649338.1 link	n.263-58166C>G		intron_variant	Intron 3 of 4
ENSG00000285679	ENST00000659022.1 link	n.972-58166C>G		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

53482

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

6096

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000175

AC:

AN:

114222

Hom.:

AF XY:

0.0000553

AC XY:

AN XY:

36194

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000413

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000139

AC:

AN:

1082009

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

352727

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000335

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000220

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

53482

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

6096

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000480

Hom.:

ExAC

AF:

0.0000265

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.283G>C (p.V95L) alteration is located in exon 3 (coding exon 2) of the VCX2 gene. This alteration results from a G to C substitution at nucleotide position 283, causing the valine (V) at amino acid position 95 to be replaced by a leucine (L). 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

0.21

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.91

DANN

Benign

0.73

DEOGEN2

Benign

0.0051

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.51

M_CAP

Benign

0.0020

MetaRNN

Benign

0.056

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.84

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.1

REVEL

Benign

0.046

Sift

Benign

0.044

Sift4G

Pathogenic

0.0

Polyphen

0.39

Vest4

0.099

MutPred

0.079

Gain of glycosylation at P94 (P = 0.0917);

MVP

0.18

MPC

0.0091

ClinPred

0.055

GERP RS

0.046

Varity_R

0.23

gMVP

0.00091

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

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