NM_016378.3:c.323G>C

Variant names:

• chrX-8170129-C-G
• rs75657421
• NM_016378.3:c.323G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_016378.3(VCX2):​c.323G>C​(p.Ser108Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (15668 hom., 3216 hem., cov: 9)
  • Exomes 𝑓: 0.77 (162123 hom. 217551 hem.)
  • Failed GnomAD Quality Control
• Consequence: VCX2 NM_016378.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.27
• Publications: 10 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.512189E-5).
• BP6: Variant X-8170129-C-G is Benign according to our data. Variant chrX-8170129-C-G is described in ClinVar as Benign. ClinVar VariationId is 769172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.323G>C	p.Ser108Thr	missense	Exon 3 of 3	NP_057462.2	Q9H322

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCX2	ENST00000317103.5	TSL:1 MANE Select	c.323G>C	p.Ser108Thr	missense	Exon 3 of 3	ENSP00000321309.4	Q9H322
	ENSG00000285679	ENST00000649338.1		n.263-58206C>G		intron	N/A
	ENSG00000285679	ENST00000659022.1		n.972-58206C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.723 AC: 43982 AN: 60821 Hom.: 15672 Cov.: 9

Gnomad AFR AF: 0.752

Gnomad AMI AF: 0.772

Gnomad AMR AF: 0.800

Gnomad ASJ AF: 0.665

Gnomad EAS AF: 0.916

Gnomad SAS AF: 0.603

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.733

Gnomad NFE AF: 0.708

Gnomad OTH AF: 0.728

GnomAD2 exomes AF: 0.771 AC: 94641 AN: 122744 AF XY: 0.715

Gnomad AFR exome AF: 0.780

Gnomad AMR exome AF: 0.875

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.937

Gnomad FIN exome AF: 0.710

Gnomad NFE exome AF: 0.726

Gnomad OTH exome AF: 0.754

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.769 AC: 593506 AN: 772169 Hom.: 162123 Cov.: 32 AF XY: 0.752 AC XY: 217551 AN XY: 289395

African (AFR) AF: 0.787 AC: 15590 AN: 19814

American (AMR) AF: 0.852 AC: 23824 AN: 27976

Ashkenazi Jewish (ASJ) AF: 0.712 AC: 10925 AN: 15336

East Asian (EAS) AF: 0.956 AC: 26526 AN: 27747

South Asian (SAS) AF: 0.774 AC: 34188 AN: 44172

European-Finnish (FIN) AF: 0.746 AC: 27242 AN: 36540

Middle Eastern (MID) AF: 0.739 AC: 1805 AN: 2441

European-Non Finnish (NFE) AF: 0.757 AC: 426126 AN: 563147

Other (OTH) AF: 0.780 AC: 27280 AN: 34996

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.723 AC: 43979 AN: 60815 Hom.: 15668 Cov.: 9 AF XY: 0.425 AC XY: 3216 AN XY: 7567

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

African (AFR) AF: 0.752 AC: 10729 AN: 14267

American (AMR) AF: 0.800 AC: 3823 AN: 4776

Ashkenazi Jewish (ASJ) AF: 0.665 AC: 1166 AN: 1754

East Asian (EAS) AF: 0.915 AC: 1489 AN: 1627

South Asian (SAS) AF: 0.603 AC: 576 AN: 955

European-Finnish (FIN) AF: 0.584 AC: 1596 AN: 2733

Middle Eastern (MID) AF: 0.767 AC: 69 AN: 90

European-Non Finnish (NFE) AF: 0.708 AC: 23697 AN: 33486

Other (OTH) AF: 0.723 AC: 533 AN: 737

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.660 Hom.: 4111

ExAC AF: 0.745 AC: 87518

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.98	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.22
DANN	Benign	0.076
DEOGEN2	Benign	0.00064	T
FATHMM_MKL	Benign	0.000040	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.000065	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-2.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.93	N
REVEL	Benign	0.018
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.091
MPC		0.0092
ClinPred		0.00061	T
GERP RS		0.046
Varity_R		0.14
gMVP		0.0018
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs75657421; hg19: chrX-8138170; COSMIC: COSV57703578;