5-76132034-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014979.4(SV2C):c.284G>A(p.Gly95Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,324 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: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SV2C NM_014979.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

SV2C (HGNC:30670): (synaptic vesicle glycoprotein 2C) Predicted to enable transmembrane transporter activity. Predicted to be involved in chemical synaptic transmission; neurotransmitter transport; and transmembrane transport. Predicted to be located in plasma membrane and synaptic vesicle. Predicted to be active in neuron projection and synaptic vesicle membrane. Predicted to be integral component of synaptic vesicle membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SV2C	NM_014979.4	c.284G>A	p.Gly95Asp	missense_variant	2/13	ENST00000502798.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SV2C	ENST00000502798.7	c.284G>A	p.Gly95Asp	missense_variant	2/13	1	NM_014979.4	P1
SV2C	ENST00000322285.7	c.284G>A	p.Gly95Asp	missense_variant	2/13	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460324 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726292

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000938 Hom.: 0

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

Dec 21, 2023

The c.284G>A (p.G95D) alteration is located in exon 2 (coding exon 1) of the SV2C gene. This alteration results from a G to A substitution at nucleotide position 284, causing the glycine (G) at amino acid position 95 to be replaced by an aspartic acid (D). 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	0.90
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.022	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.36		Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);
MVP		0.74
MPC		0.75
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.51
gMVP		0.46

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: rs1199810418; hg19: chr5-75427859;