X-55159199-C-A

Variant names:

• chrX-55159199-C-A
• rs758818648
• NM_001166701.4:c.50G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001166701.4(VCF2):​c.50G>T​(p.Gly17Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: VCF2 NM_001166701.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.264
• Publications: 7 publications found

Genes affected

VCF2 (HGNC:25085): (VCP nuclear cofactor family member 2)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07050228).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166701.4. 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
	VCF2	NM_001166701.4	MANE Select	c.50G>T	p.Gly17Val	missense	Exon 2 of 3	NP_001160173.1	A0A8I5KUH0
	VCF2	NM_001166699.2		c.50G>T	p.Gly17Val	missense	Exon 2 of 4	NP_001160171.1	Q5XKR9-2
	VCF2	NM_001166700.2		c.50G>T	p.Gly17Val	missense	Exon 2 of 3	NP_001160172.1	Q5XKR9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCF2	ENST00000685693.1	MANE Select	c.50G>T	p.Gly17Val	missense	Exon 2 of 3	ENSP00000509111.1	A0A8I5KUH0
	VCF2	ENST00000332132.8	TSL:1	c.50G>T	p.Gly17Val	missense	Exon 2 of 4	ENSP00000333394.4	Q5XKR9-2
	VCF2	ENST00000358460.8	TSL:1	c.50G>T	p.Gly17Val	missense	Exon 2 of 4	ENSP00000364101.3	Q5XKR9-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00 AC: 0 AN: 177058 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00000183 AC: 2 AN: 1090489 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 356753

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

African (AFR) AF: 0.00 AC: 0 AN: 26052

American (AMR) AF: 0.00 AC: 0 AN: 34585

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19222

East Asian (EAS) AF: 0.00 AC: 0 AN: 29906

South Asian (SAS) AF: 0.00 AC: 0 AN: 52697

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40415

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4096

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 837733

Other (OTH) AF: 0.0000218 AC: 1 AN: 45783

⚠️ 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.

GnomAD4 genome Cov.: 23

ExAC AF: 0.000264 AC: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.2
DANN	Benign	0.22
DEOGEN2	Benign	0.072	T
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.26
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.060
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.029	D
Polyphen		0.38	B
Vest4		0.24
MutPred		0.16		Loss of glycosylation at S14 (P = 0.0895)
MVP		0.040
MPC		0.25
ClinPred		0.44	T
GERP RS		-1.3
Varity_R		0.19
gMVP		0.097
Mutation Taster		=99/1	polymorphism

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: rs758818648; hg19: chrX-55185632; COSMIC: COSV59776069;