Genetic Variant NM_014312.5:c.379C>A (chr11-124750762-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_014312.5(VSIG2):c.379C>A(p.Pro127Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,416 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

VSIG2
NM_014312.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.70

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSIG2	NM_014312.5 link	c.379C>A	p.Pro127Thr	missense_variant	Exon 3 of 7	ENST00000326621.10	NP_055127.2	Q96IQ7-1
VSIG2	NM_001329920.2 link	c.379C>A	p.Pro127Thr	missense_variant	Exon 3 of 6		NP_001316849.1	Q96IQ7-2
VSIG2	XM_047426684.1 link	c.379C>A	p.Pro127Thr	missense_variant	Exon 3 of 5		XP_047282640.1
VSIG2	XM_047426685.1 link	c.62-896C>A		intron_variant	Intron 1 of 4		XP_047282641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSIG2	ENST00000326621.10 link	c.379C>A	p.Pro127Thr	missense_variant	Exon 3 of 7	1	NM_014312.5	ENSP00000318684.5		Q96IQ7-1
VSIG2	ENST00000403470.1 link	c.379C>A	p.Pro127Thr	missense_variant	Exon 3 of 6	2		ENSP00000385013.1		Q96IQ7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461416

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

726980

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000813

AC:

AN:

86082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111844

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 22, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.379C>A (p.P127T) alteration is located in exon 3 (coding exon 3) of the VSIG2 gene. This alteration results from a C to A substitution at nucleotide position 379, causing the proline (P) at amino acid position 127 to be replaced by a threonine (T). 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

0.31

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.67

D;D

MetaSVM

Benign

-0.85

MutationAssessor

Pathogenic

2.9

M;M

PhyloP100

3.7

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-7.3

D;D

REVEL

Benign

0.23

Sift

Uncertain

0.021

D;D

Sift4G

Benign

0.14

T;T

Polyphen

1.0

D;.

Vest4

0.60

MutPred

0.51

Loss of catalytic residue at P126 (P = 0.0393);Loss of catalytic residue at P126 (P = 0.0393);

MVP

0.36

MPC

0.30

ClinPred

1.0

GERP RS

5.1

Varity_R

0.59

gMVP

0.47

Mutation Taster

=78/22

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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NM_014312.5:c.379C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over