Genetic Variant VCX2:p.Asp139Asn (chrX-8170037-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_016378.3(VCX2):c.415G>A(p.Asp139Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 1,188,341 control chromosomes in the GnomAD database, including 3 homozygotes. There are 139 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D139H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., 4 hem., cov: 13)

Exomes 𝑓: 0.00039 ( 3 hom. 135 hem. )

Consequence

VCX2
NM_016378.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.15

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019512564).

BS2

High Hemizygotes in GnomAd4 at 4 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.415G>A	p.Asp139Asn	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.415G>A	p.Asp139Asn	missense	Exon 3 of 3	ENSP00000321309.4	Q9H322
ENSG00000285679	ENST00000649338.1		n.263-58298C>T		intron	N/A
ENSG00000285679	ENST00000659022.1		n.972-58298C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000229

AC:

AN:

91839

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00108

Gnomad SAS

AF:

0.000601

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000365

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000303

AC:

AN:

181495

AF XY:

0.000312

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000795

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000498

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000391

AC:

429

AN:

1096478

Hom.:

Cov.:

AF XY:

0.000372

AC XY:

135

AN XY:

362828

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26380

American (AMR)

AF:

0.0000284

AC:

AN:

35193

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19376

East Asian (EAS)

AF:

0.000133

AC:

AN:

30187

South Asian (SAS)

AF:

0.0000739

AC:

AN:

54102

European-Finnish (FIN)

AF:

0.0000757

AC:

AN:

39627

Middle Eastern (MID)

AF:

0.000264

AC:

AN:

3788

European-Non Finnish (NFE)

AF:

0.000461

AC:

388

AN:

841825

Other (OTH)

AF:

0.000522

AC:

AN:

46000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000229

AC:

AN:

91863

Hom.:

Cov.:

AF XY:

0.000231

AC XY:

AN XY:

17339

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24458

American (AMR)

AF:

0.00

AC:

AN:

8048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2336

East Asian (EAS)

AF:

0.00109

AC:

AN:

2756

South Asian (SAS)

AF:

0.000604

AC:

AN:

1655

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

179

European-Non Finnish (NFE)

AF:

0.000365

AC:

AN:

46514

Other (OTH)

AF:

0.00

AC:

AN:

1215

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.000189

Hom.:

Bravo

AF:

0.000276

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00119

AC:

ExAC

AF:

0.000398

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000475

ClinVar

ClinVar submissions

Significance:Uncertain significance

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

0.17

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.57

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0012

FATHMM_MKL

Benign

0.0023

LIST_S2

Benign

0.34

M_CAP

Benign

0.0012

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

-1.1

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.28

REVEL

Benign

0.070

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.030

Polyphen

0.98

Vest4

0.085

MVP

0.030

MPC

0.0091

ClinPred

0.047

GERP RS

0.19

Varity_R

0.090

gMVP

0.0017

Mutation Taster

=100/0

polymorphism

(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