rs587777781

Positions:

• chr1-202599351-T-G

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.920A>C​(p.Asp307Ala) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYT2 NM_177402.5 missense, splice_region
• Scores: Splicing: ADA: 0.5046
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.94

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, 3 uncertain in NM_177402.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 1-202599351-T-G is Pathogenic according to our data. Variant chr1-202599351-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 156368.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYT2	NM_177402.5	c.920A>C	p.Asp307Ala	missense_variant, splice_region_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.920A>C	p.Asp307Ala	missense_variant, splice_region_variant	8/9	1	NM_177402.5	ENSP00000356237.4
SYT2	ENST00000367267.5	c.920A>C	p.Asp307Ala	missense_variant, splice_region_variant	8/9	2		ENSP00000356236.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital myasthenic syndrome 7 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 04, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.8	H;H
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.90		Loss of ubiquitination at K311 (P = 0.0419);Loss of ubiquitination at K311 (P = 0.0419);
MVP		0.70
MPC		1.4
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.50
dbscSNV1_RF	Benign	0.53
SpliceAI score (max)		0.010		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: rs587777781; hg19: chr1-202568479;