Variant X-8170107-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000317103.5(VCX2):c.345T>A(p.Ser115Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,182,657 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 86 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., 3 hem., cov: 14)

Exomes 𝑓: 0.00018 ( 0 hom. 83 hem. )

Consequence

VCX2
ENST00000317103.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.639

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1122109).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCX2	NM_016378.3 linkuse as main transcript	c.345T>A	p.Ser115Arg	missense_variant	3/3	ENST00000317103.5	NP_057462.2	Q9H322

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
VCX2	ENST00000317103.5 linkuse as main transcript	c.345T>A	p.Ser115Arg	missense_variant	3/3	1	NM_016378.3	ENSP00000321309.4	Q9H322
ENSG00000285679	ENST00000649338.1 linkuse as main transcript	n.263-58228A>T		intron_variant
ENSG00000285679	ENST00000659022.1 linkuse as main transcript	n.972-58228A>T		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.000169

AC:

AN:

88869

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

AN XY:

16387

show subpopulations

Gnomad AFR

AF:

0.0000429

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:

0.000308

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

181571

Hom.:

AF XY:

0.0000741

AC XY:

AN XY:

67493

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:

0.000149

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.000179

AC:

196

AN:

1093788

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

362320

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000226

Gnomad4 OTH exome

AF:

0.000131

GnomAD4 genome

AF:

0.000169

AC:

AN:

88869

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

AN XY:

16387

show subpopulations

Gnomad4 AFR

AF:

0.0000429

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:

0.000308

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000829

AC:

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

May 15, 2024

The c.345T>A (p.S115R) alteration is located in exon 3 (coding exon 2) of the VCX2 gene. This alteration results from a T to A substitution at nucleotide position 345, causing the serine (S) at amino acid position 115 to be replaced by an arginine (R). 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

Uncertain

0.50

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.75

CADD

Benign

6.4

DANN

Benign

0.75

DEOGEN2

Benign

0.020

FATHMM_MKL

Benign

0.0080

LIST_S2

Benign

0.71

M_CAP

Benign

0.0036

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.036

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0080

Polyphen

0.78

Vest4

0.057

MutPred

0.15

Loss of phosphorylation at S115 (P = 0.0059);

MVP

0.088

MPC

0.0090

ClinPred

0.24

Varity_R

0.56

gMVP

0.0038

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