Genetic Variant VSTM2B:p.Ala20Val (chr19-29526642-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001146339.2(VSTM2B):c.59C>T(p.Ala20Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,377,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

VSTM2B
NM_001146339.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.29

Publications

0 publications found

Variant links:

Genes affected

VSTM2B (HGNC:33595): (V-set and transmembrane domain containing 2B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

VSTM2B links:

VSTM2B-DT (HGNC:27615): (VSTM2B divergent transcript)

VSTM2B-DT links:

LOC124904683 (HGNC:):

LOC124904683 links:

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ACMG classification

Classification was made for transcript

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=0.09464288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSTM2B	NM_001146339.2 link	c.59C>T	p.Ala20Val	missense_variant	Exon 1 of 5	ENST00000335523.8	NP_001139811.1	A6NLU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSTM2B	ENST00000335523.8 link	c.59C>T	p.Ala20Val	missense_variant	Exon 1 of 5	5	NM_001146339.2	ENSP00000335038.6		A6NLU5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000730

AC:

AN:

137030

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000424

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:

7.26e-7

AC:

AN:

1377912

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

680082

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30882

American (AMR)

AF:

0.0000284

AC:

AN:

35198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24968

East Asian (EAS)

AF:

0.00

AC:

AN:

35108

South Asian (SAS)

AF:

0.00

AC:

AN:

78072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075552

Other (OTH)

AF:

0.00

AC:

AN:

57620

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.59C>T (p.A20V) alteration is located in exon 1 (coding exon 1) of the VSTM2B gene. This alteration results from a C to T substitution at nucleotide position 59, causing the alanine (A) at amino acid position 20 to be replaced by a valine (V). 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

0.10

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0048

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.56

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.095

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.2

PhyloP100

2.3

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.35

REVEL

Benign

0.061

Sift

Benign

0.92

Sift4G

Benign

0.67

Polyphen

0.15

Vest4

0.23

MutPred

0.40

Loss of glycosylation at P15 (P = 0.1917);

MVP

0.030

ClinPred

0.31

GERP RS

2.8

Varity_R

0.040

gMVP

0.54

Mutation Taster

=82/18

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over