11-85696204-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_206927.4(SYTL2):c.6553C>A(p.Leu2185Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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)
• Consequence: SYTL2 NM_206927.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.48

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33257723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYTL2	NM_206927.4	c.6553C>A	p.Leu2185Ile	missense_variant	19/20	ENST00000359152.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYTL2	ENST00000359152.10	c.6553C>A	p.Leu2185Ile	missense_variant	19/20	1	NM_206927.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

The c.3652C>A (p.L1218I) alteration is located in exon 12 (coding exon 12) of the SYTL2 gene. This alteration results from a C to A substitution at nucleotide position 3652, causing the leucine (L) at amino acid position 1218 to be replaced by an isoleucine (I). 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	0.13
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T;T;T;.;.;T;T;T;T;T;T;T;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
REVEL	Benign	0.17
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.53	P;D;.;P;.;.;B;.;D;P;P;.;D
Vest4		0.43
MutPred		0.49		.;.;.;.;.;.;.;.;Loss of methylation at R881 (P = 0.0719);.;.;.;.;
MVP		0.79
MPC		0.078
ClinPred		0.81	D
GERP RS		6.0
Varity_R		0.15
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: chr11-85407247;