11-85707441-G-T

Variant names:

• chr11-85707441-G-T
• rs112099986
• NM_206927.4:c.6006C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_206927.4(SYTL2):​c.6006C>A​(p.Asn2002Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N2002N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SYTL2 NM_206927.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.412
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

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.6006C>A	p.Asn2002Lys	missense	Exon 15 of 20	NP_996810.2	A0A8J9FM55
	SYTL2	NM_001394447.1		c.6003C>A	p.Asn2001Lys	missense	Exon 15 of 20	NP_001381376.1
	SYTL2	NM_001394448.1		c.5958C>A	p.Asn1986Lys	missense	Exon 14 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.6006C>A	p.Asn2002Lys	missense	Exon 15 of 20	ENSP00000352065.7	A0A8J9FM55
	SYTL2	ENST00000528231.5	TSL:1	c.2091C>A	p.Asn697Lys	missense	Exon 13 of 18	ENSP00000431701.1	Q9HCH5-1
	SYTL2	ENST00000389960.8	TSL:1	c.2019C>A	p.Asn673Lys	missense	Exon 14 of 19	ENSP00000374610.4	Q9HCH5-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460638 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726682

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111062

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.32	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		-0.41
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.89
MutPred		0.79		Gain of methylation at N697 (P = 0.0062)
MVP		0.25
MPC		0.094
ClinPred		1.0	D
GERP RS		-5.7
Varity_R		0.71
gMVP		0.63
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs112099986; hg19: chr11-85418484;