Genetic Variant SV2A:p.Val708Leu (chr1-149905121-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_014849.5(SV2A):c.2122G>C(p.Val708Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V708M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SV2A
NM_014849.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.90

Publications

0 publications found

Variant links:

Genes affected

SV2A (HGNC:20566): (synaptic vesicle glycoprotein 2A) The protein encoded by this gene is one of three related synaptic vesicle proteins. The encoded protein may interact with synaptotagmin to enhance low frequency neurotransmission in quiescent neurons. [provided by RefSeq, Jun 2016]

SV2A Gene-Disease associations (from GenCC):

epilepsy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
developmental and epileptic encephalopathy 113
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

SV2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SV2A	NM_014849.5 link	c.2122G>C	p.Val708Leu	missense_variant	Exon 13 of 13	ENST00000369146.8	NP_055664.3	Q7L0J3-1
SV2A	NM_001328674.2 link	c.2122G>C	p.Val708Leu	missense_variant	Exon 13 of 13		NP_001315603.1	Q7L0J3-1
SV2A	NM_001328675.2 link	c.2122G>C	p.Val708Leu	missense_variant	Exon 13 of 13		NP_001315604.1	Q7L0J3-1
SV2A	NM_001278719.2 link	c.478G>C	p.Val160Leu	missense_variant	Exon 3 of 3		NP_001265648.1	Q7L0J3B4E000

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SV2A	ENST00000369146.8 link	c.2122G>C	p.Val708Leu	missense_variant	Exon 13 of 13	1	NM_014849.5	ENSP00000358142.3		Q7L0J3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460414

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

85800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111448

Other (OTH)

AF:

0.00

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.024

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.7

PhyloP100

7.9

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.5

REVEL

Benign

0.24

Sift

Benign

0.069

Sift4G

Uncertain

0.013

Polyphen

0.99

Vest4

0.73

MutPred

0.59

Gain of helix (P = 0.062);

MVP

0.61

MPC

1.2

ClinPred

0.94

GERP RS

4.2

Varity_R

0.18

gMVP

0.86

Mutation Taster

=46/54

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over