Genetic Variant VSIG2:p.Arg284Trp (chr11-124748391-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_014312.5(VSIG2):c.850C>T(p.Arg284Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000561 in 1,603,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

VSIG2
NM_014312.5 missense, splice_region

Scores

Splicing: ADA: 0.002123

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.183

Publications

0 publications found

Variant links:

Genes affected

VSIG2 (HGNC:17149): (V-set and immunoglobulin domain containing 2) Predicted to be located in membrane. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

VSIG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35111862).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSIG2	NM_014312.5 link	c.850C>T	p.Arg284Trp	missense_variant, splice_region_variant	Exon 6 of 7	ENST00000326621.10	NP_055127.2	Q96IQ7-1
VSIG2	NM_001329920.2 link	c.850C>T	p.Arg284Trp	missense_variant	Exon 6 of 6		NP_001316849.1	Q96IQ7-2
VSIG2	XM_047426685.1 link	c.484C>T	p.Arg162Trp	missense_variant, splice_region_variant	Exon 4 of 5		XP_047282641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSIG2	ENST00000326621.10 link	c.850C>T	p.Arg284Trp	missense_variant, splice_region_variant	Exon 6 of 7	1	NM_014312.5	ENSP00000318684.5		Q96IQ7-1
VSIG2	ENST00000403470.1 link	c.850C>T	p.Arg284Trp	missense_variant	Exon 6 of 6	2		ENSP00000385013.1		Q96IQ7-2

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151716

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000411

AC:

AN:

243496

AF XY:

0.00000760

show subpopulations

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

AF:

0.00000551

AC:

AN:

1451502

Hom.:

Cov.:

AF XY:

0.00000554

AC XY:

AN XY:

721534

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33076

American (AMR)

AF:

0.00

AC:

AN:

42488

Ashkenazi Jewish (ASJ)

AF:

0.0000393

AC:

AN:

25468

East Asian (EAS)

AF:

0.00

AC:

AN:

39596

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84896

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.00000542

AC:

AN:

1107204

Other (OTH)

AF:

0.00

AC:

AN:

59964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151716

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74074

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

41216

American (AMR)

AF:

0.0000657

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67956

Other (OTH)

AF:

0.00

AC:

AN:

2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.850C>T (p.R284W) alteration is located in exon 6 (coding exon 6) of the VSIG2 gene. This alteration results from a C to T substitution at nucleotide position 850, causing the arginine (R) at amino acid position 284 to be replaced by a tryptophan (W). 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

0.11

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;.

Eigen

Benign

-0.026

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.43

MutationAssessor

Pathogenic

3.2

M;M

PhyloP100

0.18

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.42

MVP

0.71

MPC

0.26

ClinPred

0.99

GERP RS

-2.1

Varity_R

0.30

gMVP

0.54

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0021

dbscSNV1_RF

Benign

0.30

SpliceAI score (max)

0.14

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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11-124748391-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over