6-132744311-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004665.6(VNN2):c.1552G>A(p.Val518Ile) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VNN2 NM_004665.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.182

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06351587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VNN2	NM_004665.6	c.1552G>A	p.Val518Ile	missense_variant	7/7	ENST00000326499.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VNN2	ENST00000326499.11	c.1552G>A	p.Val518Ile	missense_variant	7/7	1	NM_004665.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.1552G>A (p.V518I) alteration is located in exon 7 (coding exon 7) of the VNN2 gene. This alteration results from a G to A substitution at nucleotide position 1552, causing the valine (V) at amino acid position 518 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	4.1
Dann	Uncertain	0.98
DEOGEN2	Benign	0.015	T;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.50	T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.064	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.20	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.15	T;T;D
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0030	B;.;B
Vest4		0.14
MutPred		0.18		Gain of helix (P = 0.0696);.;.;
MVP		0.23
MPC		0.027
ClinPred		0.035	T
GERP RS		1.0
Varity_R		0.038
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-133065450;