Genetic Variant VCX2:p.Val134Ile (chrX-8170052-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_016378.3(VCX2):c.400G>A(p.Val134Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,195,230 control chromosomes in the GnomAD database, including 2 homozygotes. There are 138 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V134L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00035 ( 1 hom., 10 hem., cov: 15)

Exomes 𝑓: 0.00035 ( 1 hom. 128 hem. )

Consequence

VCX2
NM_016378.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.12

Publications

4 publications found

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 was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005207807).

BP6

Variant X-8170052-C-T is Benign according to our data. Variant chrX-8170052-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2411588.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 10 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016378.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCX2	NM_016378.3	MANE Select	c.400G>A	p.Val134Ile	missense	Exon 3 of 3	NP_057462.2	Q9H322

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VCX2	ENST00000317103.5	TSL:1 MANE Select	c.400G>A	p.Val134Ile	missense	Exon 3 of 3	ENSP00000321309.4	Q9H322
ENSG00000285679	ENST00000649338.1		n.263-58283C>T		intron	N/A
ENSG00000285679	ENST00000659022.1		n.972-58283C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

98724

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000751

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000112

Gnomad ASJ

AF:

0.00892

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000184

Gnomad OTH

AF:

0.000777

GnomAD2 exomes

AF:

0.000688

AC:

125

AN:

181740

AF XY:

0.000724

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.0126

Gnomad EAS exome

AF:

0.000361

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000174

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.000347

AC:

381

AN:

1096506

Hom.:

Cov.:

AF XY:

0.000353

AC XY:

128

AN XY:

362854

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26380

American (AMR)

AF:

0.0000284

AC:

AN:

35194

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

223

AN:

19333

East Asian (EAS)

AF:

0.000132

AC:

AN:

30201

South Asian (SAS)

AF:

0.000222

AC:

AN:

54105

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3824

European-Non Finnish (NFE)

AF:

0.000120

AC:

101

AN:

841826

Other (OTH)

AF:

0.000869

AC:

AN:

46013

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000355

AC:

AN:

98724

Hom.:

Cov.:

AF XY:

0.000449

AC XY:

AN XY:

22278

show subpopulations

African (AFR)

AF:

0.0000751

AC:

AN:

26647

American (AMR)

AF:

0.000112

AC:

AN:

8901

Ashkenazi Jewish (ASJ)

AF:

0.00892

AC:

AN:

2467

East Asian (EAS)

AF:

0.00

AC:

AN:

2999

South Asian (SAS)

AF:

0.00

AC:

AN:

1913

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4641

Middle Eastern (MID)

AF:

0.00

AC:

AN:

209

European-Non Finnish (NFE)

AF:

0.000184

AC:

AN:

49034

Other (OTH)

AF:

0.000777

AC:

AN:

1287

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000771

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000746

AC:

ExAC

AF:

0.000597

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.016

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.0012

FATHMM_MKL

Benign

0.00011

LIST_S2

Benign

0.30

M_CAP

Benign

0.0043

MetaRNN

Benign

0.0052

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.69

PhyloP100

-3.1

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.28

REVEL

Benign

0.022

Sift

Benign

0.30

Sift4G

Benign

0.69

Polyphen

0.014

Vest4

0.035

MVP

0.014

MPC

0.0094

ClinPred

0.036

GERP RS

-0.093

Varity_R

0.093

gMVP

0.0011

Mutation Taster

=100/0

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over