Genetic Variant VSTM2B:p.Ala28Gly (chr19-29527211-C-G) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001146339.2(VSTM2B):c.83C>G(p.Ala28Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000879 in 1,547,778 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 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

VSTM2B
NM_001146339.2 missense, splice_region

Scores

Splicing: ADA: 0.1782

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.03

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.41067937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSTM2B	NM_001146339.2 link	c.83C>G	p.Ala28Gly	missense_variant, splice_region_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.83C>G	p.Ala28Gly	missense_variant, splice_region_variant	Exon 2 of 5	5	NM_001146339.2	ENSP00000335038.6	A6NLU5
VSTM2B-DT	ENST00000804084.1 link	n.116+1830G>C		intron_variant	Intron 1 of 4
VSTM2B-DT	ENST00000804085.1 link	n.116+1830G>C		intron_variant	Intron 1 of 3
VSTM2B-DT	ENST00000804102.1 link	n.103+1501G>C		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000150

AC:

AN:

153374

AF XY:

0.000135

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000247

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.000462

GnomAD4 exome

AF:

0.0000881

AC:

123

AN:

1395582

Hom.:

Cov.:

AF XY:

0.0000915

AC XY:

AN XY:

688222

show subpopulations

African (AFR)

AF:

0.0000638

AC:

AN:

31336

American (AMR)

AF:

0.000197

AC:

AN:

35560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25074

East Asian (EAS)

AF:

0.00

AC:

AN:

35550

South Asian (SAS)

AF:

0.0000381

AC:

AN:

78766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48166

Middle Eastern (MID)

AF:

0.00141

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.0000863

AC:

AN:

1077570

Other (OTH)

AF:

0.000173

AC:

AN:

57872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.000523

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000925

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.83C>G (p.A28G) alteration is located in exon 2 (coding exon 2) of the VSTM2B gene. This alteration results from a C to G substitution at nucleotide position 83, causing the alanine (A) at amino acid position 28 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

Benign

0.15

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.49

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.039

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.41

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

4.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.24

Sift

Benign

0.054

Sift4G

Benign

0.10

Polyphen

0.99

Vest4

0.49

MVP

0.18

ClinPred

0.19

GERP RS

4.5

Varity_R

0.30

gMVP

0.53

Mutation Taster

=31/69

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.18

dbscSNV1_RF

Benign

0.32

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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19-29527211-C-G

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