chrX-8170052-C-T

Variant names:

• chrX-8170052-C-T
• rs148114540
• NM_016378.3:c.400G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• 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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.12

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]

ENSG00000285679 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 2411588.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-8170052-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCX2	NM_016378.3	c.400G>A	p.Val134Ile	missense_variant	Exon 3 of 3	ENST00000317103.5	NP_057462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCX2	ENST00000317103.5	c.400G>A	p.Val134Ile	missense_variant	Exon 3 of 3	1	NM_016378.3	ENSP00000321309.4
ENSG00000285679	ENST00000649338.1	n.263-58283C>T		intron_variant	Intron 3 of 4
ENSG00000285679	ENST00000659022.1	n.972-58283C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 35 AN: 98724 Hom.: 1 Cov.: 15 AF XY: 0.000449 AC XY: 10 AN XY: 22278

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

GnomAD3 exomes AF: 0.000688 AC: 125 AN: 181740 Hom.: 0 AF XY: 0.000724 AC XY: 49 AN XY: 67640

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 SAS exome AF: 0.000315

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.: 1 Cov.: 76 AF XY: 0.000353 AC XY: 128 AN XY: 362854

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.0115

Gnomad4 EAS exome AF: 0.000132

Gnomad4 SAS exome AF: 0.000222

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.000869

GnomAD4 genome AF: 0.000355 AC: 35 AN: 98724 Hom.: 1 Cov.: 15 AF XY: 0.000449 AC XY: 10 AN XY: 22278

Gnomad4 AFR AF: 0.0000751

Gnomad4 AMR AF: 0.000112

Gnomad4 ASJ AF: 0.00892

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000184

Gnomad4 OTH AF: 0.000777

Alfa AF: 0.000774 Hom.: 16

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000746 AC: 5

ExAC AF: 0.000597 AC: 72

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 09, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.016
DANN	Benign	0.75
DEOGEN2	Benign	0.0012	T
FATHMM_MKL	Benign	0.00011	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.69	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.022
Sift	Benign	0.30	T
Sift4G	Benign	0.69	T
Polyphen		0.014	B
Vest4		0.035
MVP		0.014
MPC		0.0094
ClinPred		0.036	T
GERP RS		-0.093
Varity_R		0.093
gMVP		0.0011

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

Other links and lift over

dbSNP: rs148114540; hg19: chrX-8138093; COSMIC: COSV57703900;