Genetic Variant VNN2:p.Arg463Pro (chr6-132744475-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_004665.6(VNN2):c.1388G>C(p.Arg463Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R463H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

VNN2
NM_004665.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.18

Publications

0 publications found

Variant links:

Genes affected

VNN2 (HGNC:12706): (vanin 2) This gene product is a member of the Vanin family of proteins that share extensive sequence similarity with each other, and also with biotinidase. The family includes secreted and membrane-associated proteins, a few of which have been reported to participate in hematopoietic cell trafficking. No biotinidase activity has been demonstrated for any of the vanin proteins, however, they possess pantetheinase activity, which may play a role in oxidative-stress response. The encoded protein is a GPI-anchored cell surface molecule that plays a role in transendothelial migration of neutrophils. This gene lies in close proximity to, and in same transcriptional orientation as two other vanin genes on chromosome 6q23-q24. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, May 2011]

VNN2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VNN2	NM_004665.6 link	c.1388G>C	p.Arg463Pro	missense_variant	Exon 7 of 7	ENST00000326499.11	NP_004656.3	O95498-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VNN2	ENST00000326499.11 link	c.1388G>C	p.Arg463Pro	missense_variant	Exon 7 of 7	1	NM_004665.6	ENSP00000322276.6		O95498-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1427490

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31484

American (AMR)

AF:

0.00

AC:

AN:

36190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24854

East Asian (EAS)

AF:

0.00

AC:

AN:

38154

South Asian (SAS)

AF:

0.00

AC:

AN:

79724

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

9.10e-7

AC:

AN:

1099406

Other (OTH)

AF:

0.00

AC:

AN:

58940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Uncertain

0.090

MetaRNN

Pathogenic

0.76

D;D;D

MetaSVM

Uncertain

0.39

MutationAssessor

Uncertain

2.8

M;.;.

PhyloP100

3.2

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Pathogenic

0.75

Sift

Benign

0.035

D;T;D

Sift4G

Uncertain

0.022

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.53

MutPred

0.57

Gain of ubiquitination at K467 (P = 0.0444);.;.;

MVP

0.80

MPC

0.18

ClinPred

0.99

GERP RS

4.5

Varity_R

0.88

gMVP

0.63

Mutation Taster

=71/29

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over