rs587777782

Variant names:

• chr1-202599348-G-A
• rs587777782
• NM_177402.5:c.923C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM1 PM2 PP2 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002240812: Experimental studies have shown that this missense change affects SYT2 function (PMID:28953919).". 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
• Publications: 11 publications found

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]

SYT2 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002240812: Experimental studies have shown that this missense change affects SYT2 function (PMID: 28953919).
• 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
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.9784 (below the threshold of 3.09). Trascript score misZ: 2.5575 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital myasthenic syndrome 7, presynaptic congenital myasthenic syndrome, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive.
• 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 VariationId is 156369.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177402.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT2	NM_177402.5	MANE Select	c.923C>T	p.Pro308Leu	missense	Exon 8 of 9	NP_796376.2
	SYT2	NM_001136504.1		c.923C>T	p.Pro308Leu	missense	Exon 8 of 9	NP_001129976.1	Q8N9I0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT2	ENST00000367268.5	TSL:1 MANE Select	c.923C>T	p.Pro308Leu	missense	Exon 8 of 9	ENSP00000356237.4	Q8N9I0
	SYT2	ENST00000930883.1		c.983C>T	p.Pro328Leu	missense	Exon 8 of 9	ENSP00000600942.1
	SYT2	ENST00000899895.1		c.932C>T	p.Pro311Leu	missense	Exon 8 of 9	ENSP00000569954.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	-	-	Congenital myasthenic syndrome 7 (4)
-	1	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		9.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.9	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.84		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
Mutation Taster		=8/92	disease causing

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

Other links and lift over

dbSNP: rs587777782; hg19: chr1-202568476;