Genetic Variant VSTM2B:p.Trp66Gly (chr19-29527324-T-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001146339.2(VSTM2B):c.196T>G(p.Trp66Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

VSTM2B
NM_001146339.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.99

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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSTM2B	NM_001146339.2 link	c.196T>G	p.Trp66Gly	missense_variant	Exon 2 of 5	ENST00000335523.8	NP_001139811.1	A6NLU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VSTM2B	ENST00000335523.8 link	c.196T>G	p.Trp66Gly	missense_variant	Exon 2 of 5	5	NM_001146339.2	ENSP00000335038.6	A6NLU5
VSTM2B-DT	ENST00000804084.1 link	n.116+1717A>C		intron_variant	Intron 1 of 4
VSTM2B-DT	ENST00000804085.1 link	n.116+1717A>C		intron_variant	Intron 1 of 3
VSTM2B-DT	ENST00000804102.1 link	n.103+1388A>C		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000648

AC:

AN:

154208

AF XY:

0.00

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:

7.16e-7

AC:

AN:

1397610

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31518

American (AMR)

AF:

0.00

AC:

AN:

35686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25156

East Asian (EAS)

AF:

0.00

AC:

AN:

35690

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078710

Other (OTH)

AF:

0.00

AC:

AN:

57948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000411

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.196T>G (p.W66G) alteration is located in exon 2 (coding exon 2) of the VSTM2B gene. This alteration results from a T to G substitution at nucleotide position 196, causing the tryptophan (W) at amino acid position 66 to be replaced by a glycine (G). 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

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

-0.017

MutationAssessor

Pathogenic

3.2

PhyloP100

8.0

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-12

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.91

MutPred

0.83

Loss of stability (P = 0.0301);

MVP

0.44

ClinPred

1.0

GERP RS

4.5

Varity_R

0.97

gMVP

0.91

Mutation Taster

=13/87

disease causing

(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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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