chr15-91252371-T-C

Position:

• chr15-91252371-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001323032.3(SV2B):​c.635T>C​(p.Ile212Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000762 in 1,610,024 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00055 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (1 hom.)
• Consequence: SV2B NM_001323032.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.91

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01856199).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SV2B	NM_001323032.3	c.635T>C	p.Ile212Thr	missense_variant, splice_region_variant	4/13	ENST00000394232.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SV2B	ENST00000394232.6	c.635T>C	p.Ile212Thr	missense_variant, splice_region_variant	4/13	5	NM_001323032.3	P1
SV2B	ENST00000330276.4	c.635T>C	p.Ile212Thr	missense_variant, splice_region_variant	3/12	1		P1
SV2B	ENST00000557410.5	c.635T>C	p.Ile212Thr	missense_variant, splice_region_variant, NMD_transcript_variant	5/15	1
SV2B	ENST00000545111.6	c.182T>C	p.Ile61Thr	missense_variant, splice_region_variant	3/12	2

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000679 AC: 167 AN: 245864 Hom.: 0 AF XY: 0.000661 AC XY: 88 AN XY: 133036

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000889

Gnomad ASJ exome AF: 0.00835

Gnomad EAS exome AF: 0.000166

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000649

Gnomad OTH exome AF: 0.000672

GnomAD4 exome AF: 0.000784 AC: 1143 AN: 1457734 Hom.: 1 Cov.: 31 AF XY: 0.000764 AC XY: 554 AN XY: 725028

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000159

Gnomad4 ASJ exome AF: 0.00816

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000564

Gnomad4 NFE exome AF: 0.000747

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74470

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000954 Hom.: 0

Bravo AF: 0.000620

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000651 AC: 79

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

Oct 18, 2021

The c.635T>C (p.I212T) 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 635, causing the isoleucine (I) at amino acid position 212 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	0.27
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	.;D;D
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;.;D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.019	T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.3	.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.25	.;B;B
Vest4		0.74
MVP		0.40
MPC		0.39
ClinPred		0.060	T
GERP RS		4.2
Varity_R		0.34
gMVP		0.80

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: rs145534909; hg19: chr15-91795601;