Genetic Variant VCF2:p.Cys4Tyr (chrX-55161146-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001166701.4(VCF2):c.11G>A(p.Cys4Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,206,843 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 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. C4F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000026 ( 0 hom. 11 hem. )

Consequence

VCF2
NM_001166701.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.00

Publications

0 publications found

Variant links:

Genes affected

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

VCF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11380571).

BS2

High Hemizygotes in GnomAdExome4 at 11 gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VCF2	NM_001166701.4	MANE Select	c.11G>A	p.Cys4Tyr	missense	Exon 1 of 3	NP_001160173.1	A0A8I5KUH0
VCF2	NM_001166699.2		c.11G>A	p.Cys4Tyr	missense	Exon 1 of 4	NP_001160171.1	Q5XKR9-2
VCF2	NM_001166700.2		c.11G>A	p.Cys4Tyr	missense	Exon 1 of 3	NP_001160172.1	Q5XKR9-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VCF2	ENST00000685693.1	MANE Select	c.11G>A	p.Cys4Tyr	missense	Exon 1 of 3	ENSP00000509111.1	A0A8I5KUH0
VCF2	ENST00000332132.8	TSL:1	c.11G>A	p.Cys4Tyr	missense	Exon 1 of 4	ENSP00000333394.4	Q5XKR9-2
VCF2	ENST00000358460.8	TSL:1	c.11G>A	p.Cys4Tyr	missense	Exon 1 of 4	ENSP00000364101.3	Q5XKR9-1

Frequencies

GnomAD3 genomes

AF:

0.00000888

AC:

AN:

112580

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000117

AC:

AN:

171155

AF XY:

0.0000344

show subpopulations

Gnomad AFR exome

AF:

0.0000836

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:

0.0000256

AC:

AN:

1094263

Hom.:

Cov.:

AF XY:

0.0000305

AC XY:

AN XY:

360181

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

26357

American (AMR)

AF:

0.00

AC:

AN:

34874

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19282

East Asian (EAS)

AF:

0.00

AC:

AN:

30068

South Asian (SAS)

AF:

0.0000563

AC:

AN:

53312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.0000250

AC:

AN:

840182

Other (OTH)

AF:

0.00

AC:

AN:

45936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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

AF:

0.00000888

AC:

AN:

112580

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34738

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30986

American (AMR)

AF:

0.00

AC:

AN:

10801

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3535

South Asian (SAS)

AF:

0.00

AC:

AN:

2716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6219

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53215

Other (OTH)

AF:

0.00

AC:

AN:

1535

Age Distribution

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:

0.00

Hom.:

Bravo

AF:

0.0000378

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

0.24

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.040

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.48

M_CAP

Benign

0.0058

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

-1.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.7

REVEL

Benign

0.036

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

0.71

Vest4

0.24

MutPred

0.29

Loss of catalytic residue at V6 (P = 0.0943)

MVP

0.20

MPC

0.57

ClinPred

0.14

GERP RS

-0.92

PromoterAI

-0.059

Neutral

(source)

Varity_R

0.43

gMVP

0.062

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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