rs587777782

Positions:

• chr1-202599348-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_177402.5(SYT2):​c.923C>T​(p.Pro308Leu) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P308P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYT2 NM_177402.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 9.90

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_177402.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 1-202599348-G-A is Pathogenic according to our data. Variant chr1-202599348-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 156369.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYT2	NM_177402.5	c.923C>T	p.Pro308Leu	missense_variant	8/9	ENST00000367268.5	NP_796376.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYT2	ENST00000367268.5	c.923C>T	p.Pro308Leu	missense_variant	8/9	1	NM_177402.5	ENSP00000356237.4
SYT2	ENST00000367267.5	c.923C>T	p.Pro308Leu	missense_variant	8/9	2		ENSP00000356236.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myasthenic syndrome 7 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 04, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 04, 2022	The SYT2 c.923C>T variant is classified as Likely Pathogenic (PS4_supporting, PM2, PP1_strong, PP3) The SYT2 c.923C>T variant is a single nucleotide change in exon 8/9 of the SYT2 gene, which is predicted to change the amino acid proline at position 308 in the protein to leucine. This variant has been reported to co-segregate with disease in a UK family with several affected individuals over four generations. This family presented with childhood-onset foot deformities, lower limb weakness and wasting with areflexia. In some cases additional fatigability of the eye and limb muscles was observed (PMID:26519543, PMID:26519543) (PS4_supporting, PP1-strong). This variant is in dbSNP (rs587777782), but is absent from population databases (PM2). This variant has been reported in ClinVar as pathogenic for Myasthenic syndrome, congenital, presynaptic by another diagnostic laboratory (ClinVar Variation ID: 156369) and also as damaging for nonprogressive motor neuropathy in the disease database HGMD (CM149796). Computational predictions support a deleterious effect on the gene or gene product (PP3). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 17, 2024	PS3_Moderate, PS4_Supporting, PM2, PP1, PP3 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 15, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SYT2 function (PMID: 28953919). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 156369). This missense change has been observed in individual(s) with autosomal dominant congenital myasthenic syndrome (PMID: 25192047). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 308 of the SYT2 protein (p.Pro308Leu). -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.5	H;H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.9	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.84		Gain of MoRF binding (P = 0.0602);Gain of MoRF binding (P = 0.0602);
MVP		0.79
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.88
gMVP		0.90

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: rs587777782; hg19: chr1-202568476;