Genetic Variant VCX2:p.Pro103Pro (chrX-8170143-G-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_016378.3(VCX2):c.309C>G(p.Pro103Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000003 in 999,350 control chromosomes in the GnomAD database, including 1 homozygotes. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P103P) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.0000030 ( 1 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

VCX2
NM_016378.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.42

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.11).

BP7

Synonymous conserved (PhyloP=-2.41 with no splicing effect.

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.309C>G	p.Pro103Pro	synonymous	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.309C>G	p.Pro103Pro	synonymous	Exon 3 of 3	ENSP00000321309.4	Q9H322
ENSG00000285679	ENST00000649338.1		n.263-58192G>C		intron	N/A
ENSG00000285679	ENST00000659022.1		n.972-58192G>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

57399

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00

AC:

AN:

90592

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000300

AC:

AN:

999350

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

305998

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24250

American (AMR)

AF:

0.00

AC:

AN:

31196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18095

East Asian (EAS)

AF:

0.00

AC:

AN:

28962

South Asian (SAS)

AF:

0.00

AC:

AN:

48736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36489

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2711

European-Non Finnish (NFE)

AF:

0.00000391

AC:

AN:

766338

Other (OTH)

AF:

0.00

AC:

AN:

42573

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

57399

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

6741

African (AFR)

AF:

0.00

AC:

AN:

13720

American (AMR)

AF:

0.00

AC:

AN:

4259

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1708

East Asian (EAS)

AF:

0.00

AC:

AN:

1448

South Asian (SAS)

AF:

0.00

AC:

AN:

879

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

31678

Other (OTH)

AF:

0.00

AC:

AN:

631

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.1

CADD

Benign

2.1

(source)

DANN

Benign

0.45

PhyloP100

-2.4

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over