NM_001394072.1:c.11C>T

Variant names:

• chr11-1835116-C-T
• rs754478962
• NM_001394072.1:c.11C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001394072.1(SYT8):​c.11C>T​(p.Pro4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,460,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: SYT8 NM_001394072.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.701
• Publications: 0 publications found

Genes affected

SYT8 (HGNC:19264): (synaptotagmin 8) This gene encodes a member of the synaptotagmin protein family. Synaptotagmins are membrane proteins that are important in neurotransmission and hormone secretion, both of which involve regulated exocytosis. Expression of the encoded protein in human pancreatic islets has been connected to activity of the promoter for the insulin gene, on the same chromosome several hundred kilobases away (PMID: 21336277 and 22928559). This association would link response to gluclose to insulin secretion. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048054695).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394072.1. 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
	SYT8	NM_001394072.1	MANE Select	c.11C>T	p.Pro4Leu	missense	Exon 1 of 8	NP_001381001.1	Q8NBV8-4
	SYT8	NM_001290332.2		c.56C>T	p.Pro19Leu	missense	Exon 2 of 9	NP_001277261.2
	SYT8	NM_001290333.2		c.53C>T	p.Pro18Leu	missense	Exon 2 of 9	NP_001277262.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT8	ENST00000341958.4	TSL:5 MANE Select	c.11C>T	p.Pro4Leu	missense	Exon 1 of 8	ENSP00000343691.3	Q8NBV8-4
	SYT8	ENST00000381978.7	TSL:1	c.47C>T	p.Pro16Leu	missense	Exon 2 of 9	ENSP00000371406.3	H0Y3G9
	SYT8	ENST00000482118.1	TSL:1	n.11C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250372 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1460976 Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20 AN XY: 726794

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52720

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111902

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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	Benign	0.078
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Benign	0.63
DEOGEN2	Benign	0.0084	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0071	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.70
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.035
Sift	Benign	0.32	T
Sift4G	Uncertain	0.014	D
Polyphen		0.27	B
Vest4		0.14
MutPred		0.42		Loss of glycosylation at P18 (P = 0.0461)
MVP		0.28
MPC		0.075
ClinPred		0.18	T
GERP RS		0.76
PromoterAI		-0.025	Neutral
Varity_R		0.037
gMVP		0.25
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs754478962; hg19: chr11-1856346;