1-202596923-A-G

Position:

• chr1-202596923-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_Moderate PM1 PM2 PP5_Moderate

The NM_177402.5(SYT2):​c.1094T>C​(p.Leu365Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SYT2 NM_177402.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.25

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 8 ACMG points.

• PS1: Transcript NM_177402.5 (SYT2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a region_of_interest Phospholipid binding (size 246) in uniprot entity SYT2_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_177402.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-202596923-A-G is Pathogenic according to our data. Variant chr1-202596923-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1192313.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYT2	NM_177402.5	c.1094T>C	p.Leu365Pro	missense_variant	9/9	ENST00000367268.5	NP_796376.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYT2	ENST00000367268.5	c.1094T>C	p.Leu365Pro	missense_variant	9/9	1	NM_177402.5	ENSP00000356237.4
SYT2	ENST00000367267.5	c.1094T>C	p.Leu365Pro	missense_variant	9/9	2		ENSP00000356236.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 07, 2023

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 1192313). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 34037996). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 365 of the SYT2 protein (p.Leu365Pro). -

Congenital myasthenic syndrome 7 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 06, 2021

- -

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	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.089	T;T
Polyphen		1.0	D;D
Vest4		0.45
MutPred		0.55		Loss of stability (P = 0.0068);Loss of stability (P = 0.0068);
MVP		0.51
MPC		2.9
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.84
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-202566051; COSMIC: COSV100937126; COSMIC: COSV100937126;