chr11-85698035-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206927.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYTL2	NM_206927.4	MANE Select	c.6312G>C	p.Lys2104Asn	missense	Exon 18 of 20	NP_996810.2	A0A8J9FM55
	SYTL2	NM_001394447.1		c.6309G>C	p.Lys2103Asn	missense	Exon 18 of 20	NP_001381376.1
	SYTL2	NM_001394448.1		c.6264G>C	p.Lys2088Asn	missense	Exon 17 of 19	NP_001381377.1	A0A0U1RR07

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYTL2	ENST00000359152.10	TSL:1 MANE Select	c.6312G>C	p.Lys2104Asn	missense	Exon 18 of 20	ENSP00000352065.7	A0A8J9FM55
	SYTL2	ENST00000528231.5	TSL:1	c.2397G>C	p.Lys799Asn	missense	Exon 16 of 18	ENSP00000431701.1	Q9HCH5-1
	SYTL2	ENST00000389960.8	TSL:1	c.2325G>C	p.Lys775Asn	missense	Exon 17 of 19	ENSP00000374610.4	Q9HCH5-6

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.93
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	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
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs2083670011; hg19: chr11-85409078;