1-202604576-A-T

Variant names:

• chr1-202604576-A-T
• NM_177402.5:c.224T>A

Variant summary

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

The NM_177402.5(SYT2):​c.224T>A​(p.Leu75Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L75L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYT2 NM_177402.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.34

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)

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, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYT2	NM_177402.5	c.224T>A	p.Leu75Gln	missense_variant	Exon 3 of 9	ENST00000367268.5	NP_796376.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYT2	ENST00000367268.5	c.224T>A	p.Leu75Gln	missense_variant	Exon 3 of 9	1	NM_177402.5	ENSP00000356237.4
SYT2	ENST00000367267.5	c.224T>A	p.Leu75Gln	missense_variant	Exon 3 of 9	2		ENSP00000356236.1
ENSG00000226862	ENST00000428573.1	n.68+241A>T		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 expected to disrupt SYT2 protein function. This variant has not been reported in the literature in individuals affected with SYT2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 75 of the SYT2 protein (p.Leu75Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.87	D;D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Pathogenic	3.5	H;H
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.83	P;P
Vest4		0.87
MutPred		0.35		Gain of catalytic residue at L75 (P = 0.0107);Gain of catalytic residue at L75 (P = 0.0107);
MVP		0.15
MPC		0.61
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.68
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.42		Position offset: -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: chr1-202573704; COSMIC: COSV66142413;