Genetic Variant SV2B:p.Met253Thr (chr15-91252494-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001323032.3(SV2B):c.758T>C(p.Met253Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,612,282 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SV2B
NM_001323032.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.98

Variant links:

Genes affected

SV2B (HGNC:16874): (synaptic vesicle glycoprotein 2B) This gene encodes a member of the synaptic vesicle proteins 2 (SV2) family and major facilitator superfamily of proteins. This protein and other members of the family are localized to synaptic vesicles and may function in the regulation of vesicle trafficking and exocytosis. Studies in mice suggest that the encoded protein may act as a protein receptor for botulinum neurotoxin E in neurons, and that this protein may be important for the integrity of the glomerular filtration barrier. This gene shows reduced expression in areas of synaptic loss in the hippocampus of human temporal lobe epilepsy patients. [provided by RefSeq, Sep 2016]

SV2B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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
SV2B	NM_001323032.3 link	c.758T>C	p.Met253Thr	missense_variant	Exon 4 of 13	ENST00000394232.6	NP_001309961.1	Q7L1I2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SV2B	ENST00000394232.6 link	c.758T>C	p.Met253Thr	missense_variant	Exon 4 of 13	5	NM_001323032.3	ENSP00000377779.1	Q7L1I2-1
SV2B	ENST00000330276.4 link	c.758T>C	p.Met253Thr	missense_variant	Exon 3 of 12	1		ENSP00000332818.4	Q7L1I2-1
SV2B	ENST00000557410.5 link	n.758T>C		non_coding_transcript_exon_variant	Exon 5 of 15	1		ENSP00000450992.1	Q7L1I2-1
SV2B	ENST00000545111.6 link	c.305T>C	p.Met102Thr	missense_variant	Exon 3 of 12	2		ENSP00000443243.2	Q7L1I2-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249320

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000550

Gnomad SAS 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:

0.00000137

AC:

AN:

1460092

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726276

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.0000553

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.758T>C (p.M253T) alteration is located in exon 5 (coding exon 3) of the SV2B gene. This alteration results from a T to C substitution at nucleotide position 758, causing the methionine (M) at amino acid position 253 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

0.26

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.53

.;D;D

Eigen

Benign

-0.12

Eigen_PC

Benign

0.051

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

D;.;D

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.56

D;D;D

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.92

.;L;L

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.4

N;D;D

REVEL

Benign

0.20

Sift

Benign

0.15

T;T;T

Sift4G

Benign

0.28

T;T;T

Polyphen

0.0060

.;B;B

Vest4

0.71

MutPred

0.74

.;Loss of stability (P = 0.0741);Loss of stability (P = 0.0741);

MVP

0.23

MPC

0.33

ClinPred

0.25

GERP RS

4.3

Varity_R

0.34

gMVP

0.77

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over