11-124749715-C-T

Variant names:

• chr11-124749715-C-T
• rs530449056
• NM_014312.5:c.579G>A

Variant summary

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

The NM_014312.5(VSIG2):​c.579G>A​(p.Met193Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,612,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: VSIG2 NM_014312.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50
• Publications: 1 publications found

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]

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=0.14590383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSIG2	NM_014312.5	c.579G>A	p.Met193Ile	missense_variant	Exon 4 of 7	ENST00000326621.10	NP_055127.2
VSIG2	NM_001329920.2	c.579G>A	p.Met193Ile	missense_variant	Exon 4 of 6		NP_001316849.1
VSIG2	XM_047426684.1	c.579G>A	p.Met193Ile	missense_variant	Exon 4 of 5		XP_047282640.1
VSIG2	XM_047426685.1	c.213G>A	p.Met71Ile	missense_variant	Exon 2 of 5		XP_047282641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSIG2	ENST00000326621.10	c.579G>A	p.Met193Ile	missense_variant	Exon 4 of 7	1	NM_014312.5	ENSP00000318684.5
VSIG2	ENST00000403470.1	c.579G>A	p.Met193Ile	missense_variant	Exon 4 of 6	2		ENSP00000385013.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151920 Hom.: 0 Cov.: 30

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250012 AF XY: 0.00000740

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1460784 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726700

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111598

Other (OTH) AF: 0.0000166 AC: 1 AN: 60352

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151920 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74212

African (AFR) AF: 0.00 AC: 0 AN: 41330

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.579G>A (p.M193I) alteration is located in exon 4 (coding exon 4) of the VSIG2 gene. This alteration results from a G to A substitution at nucleotide position 579, causing the methionine (M) at amino acid position 193 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	0.23
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.023	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.56	N;N
PhyloP100		2.5
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.77	N;N
REVEL	Benign	0.094
Sift	Benign	0.16	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.0020	B;.
Vest4		0.35
MutPred		0.38		Gain of catalytic residue at M193 (P = 0.0024);Gain of catalytic residue at M193 (P = 0.0024);
MVP		0.31
MPC		0.045
ClinPred		0.28	T
GERP RS		4.6
Varity_R		0.16
gMVP		0.37
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs530449056; hg19: chr11-124619611;