rs2083670011

Variant names:

• chr11-85698035-C-G
• rs2083670011
• NM_206927.4:c.6312G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_206927.4(SYTL2):​c.6312G>C​(p.Lys2104Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SYTL2 NM_206927.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.934

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYTL2	NM_206927.4	c.6312G>C	p.Lys2104Asn	missense_variant	Exon 18 of 20	ENST00000359152.10	NP_996810.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYTL2	ENST00000359152.10	c.6312G>C	p.Lys2104Asn	missense_variant	Exon 18 of 20	1	NM_206927.4	ENSP00000352065.7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3411G>C (p.K1137N) alteration is located in exon 11 (coding exon 11) of the SYTL2 gene. This alteration results from a G to C substitution at nucleotide position 3411, causing the lysine (K) at amino acid position 1137 to be replaced by an asparagine (N). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;.;.;.;.;.;.;T;T;.;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D;.;.;D;D;D;D;D;D;D;.
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Pathogenic	3.2	.;.;.;.;.;.;.;.;M;.;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.6	.;D;.;D;D;D;D;.;D;D;D;.;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0020	.;D;.;D;D;D;D;.;D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;.;D;.;D;D;D;.;D
Vest4		0.80
MutPred		0.56		.;.;.;.;.;.;.;.;Loss of ubiquitination at K799 (P = 0.0412);.;.;.;.;
MVP		0.82
MPC		0.094
ClinPred		1.0	D
GERP RS		2.9
Varity_R		0.81
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2083670011; hg19: chr11-85409078;