chr15-91252515-A-G

Position:

• chr15-91252515-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001323032.3(SV2B):​c.779A>G​(p.His260Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,454,160 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: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SV2B NM_001323032.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SV2B	NM_001323032.3	c.779A>G	p.His260Arg	missense_variant	4/13	ENST00000394232.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SV2B	ENST00000394232.6	c.779A>G	p.His260Arg	missense_variant	4/13	5	NM_001323032.3	P1
SV2B	ENST00000330276.4	c.779A>G	p.His260Arg	missense_variant	3/12	1		P1
SV2B	ENST00000557410.5	c.779A>G	p.His260Arg	missense_variant, NMD_transcript_variant	5/15	1
SV2B	ENST00000545111.6	c.326A>G	p.His109Arg	missense_variant	3/12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454160 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722922

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The c.779A>G (p.H260R) alteration is located in exon 5 (coding exon 3) of the SV2B gene. This alteration results from a A to G substitution at nucleotide position 779, causing the histidine (H) at amino acid position 260 to be replaced by an arginine (R). 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	0.17
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	.;T;T
Eigen	Benign	-0.013
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.86	.;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.22	.;B;B
Vest4		0.88
MutPred		0.80		.;Gain of MoRF binding (P = 0.045);Gain of MoRF binding (P = 0.045);
MVP		0.52
MPC		0.51
ClinPred		0.84	D
GERP RS		5.3
Varity_R		0.30
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

Other links and lift over

dbSNP: rs2047528529; hg19: chr15-91795745; COSMIC: COSV57700174; COSMIC: COSV57700174;