1-202604462-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_177402.5(SYT2):​c.338G>A​(p.Gly113Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SYT2
NM_177402.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.72
Variant links:
Genes affected
SYT2 (HGNC:11510): (synaptotagmin 2) This gene encodes a synaptic vesicle membrane protein. The encoded protein is thought to function as a calcium sensor in vesicular trafficking and exocytosis. Mutations in this gene are associated with myasthenic syndrome, presynaptic, congenital, with or without motor neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]
ENSG00000226862 (HGNC:40572): (SYT2 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23874477).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYT2NM_177402.5 linkc.338G>A p.Gly113Glu missense_variant Exon 3 of 9 ENST00000367268.5 NP_796376.2 Q8N9I0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SYT2ENST00000367268.5 linkc.338G>A p.Gly113Glu missense_variant Exon 3 of 9 1 NM_177402.5 ENSP00000356237.4 Q8N9I0
SYT2ENST00000367267.5 linkc.338G>A p.Gly113Glu missense_variant Exon 3 of 9 2 ENSP00000356236.1 Q8N9I0
ENSG00000226862ENST00000428573.1 linkn.68+127C>T intron_variant Intron 1 of 1 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461796
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727190
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jan 19, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.338G>A (p.G113E) alteration is located in exon 3 (coding exon 2) of the SYT2 gene. This alteration results from a G to A substitution at nucleotide position 338, causing the glycine (G) at amino acid position 113 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1
May 07, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 113 of the SYT2 protein (p.Gly113Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SYT2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SYT2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Benign
-0.090
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.28
T;T
Eigen
Benign
-0.040
Eigen_PC
Benign
0.079
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.80
.;T
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.24
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.53
N;N
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.38
N;N
REVEL
Benign
0.21
Sift
Benign
0.16
T;T
Sift4G
Benign
0.53
T;T
Polyphen
0.79
P;P
Vest4
0.49
MutPred
0.19
Loss of MoRF binding (P = 0.0718);Loss of MoRF binding (P = 0.0718);
MVP
0.31
MPC
0.25
ClinPred
0.59
D
GERP RS
4.8
Varity_R
0.17
gMVP
0.46

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-202573590; COSMIC: COSV105298224; API