11-85700518-G-A

Variant names:

• chr11-85700518-G-A
• rs1403164799
• NM_206927.4:c.6265C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_206927.4(SYTL2):​c.6265C>T​(p.Pro2089Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 1,458,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SYTL2 NM_206927.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57

Genes affected

SYTL2 (HGNC:15585): (synaptotagmin like 2) The protein encoded by this gene is a synaptotagmin-like protein (SLP) that belongs to a C2 domain-containing protein family. The SLP homology domain (SHD) of this protein has been shown to specifically bind the GTP-bound form of Ras-related protein Rab-27A (RAB27A). This protein plays a role in RAB27A-dependent vesicle trafficking and controls melanosome distribution in the cell periphery. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0779393).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYTL2	NM_206927.4	c.6265C>T	p.Pro2089Ser	missense_variant	Exon 17 of 20	ENST00000359152.10	NP_996810.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYTL2	ENST00000359152.10	c.6265C>T	p.Pro2089Ser	missense_variant	Exon 17 of 20	1	NM_206927.4	ENSP00000352065.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1458556 Hom.: 0 Cov.: 30 AF XY: 0.00000689 AC XY: 5 AN XY: 725902

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3364C>T (p.P1122S) alteration is located in exon 10 (coding exon 10) of the SYTL2 gene. This alteration results from a C to T substitution at nucleotide position 3364, causing the proline (P) at amino acid position 1122 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Benign	0.61
DEOGEN2	Benign	0.020	.;.;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.86	D;D;T;.;.;T;T;T;D;T;D;T;.
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.078	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	.;.;.;.;.;.;.;.;N;.;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.89	.;N;.;N;N;N;N;.;N;N;N;.;N
REVEL	Benign	0.045
Sift	Benign	0.33	.;T;.;T;T;T;T;.;T;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0070	B;B;.;B;.;.;B;.;B;B;B;.;B
Vest4		0.087
MutPred		0.29		.;.;.;.;.;.;.;.;Loss of ubiquitination at K787 (P = 0.0561);.;.;.;.;
MVP		0.47
MPC		0.016
ClinPred		0.23	T
GERP RS		3.0
Varity_R		0.043
gMVP		0.29

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: rs1403164799; hg19: chr11-85411561; COSMIC: COSV60358677; COSMIC: COSV60358677;