rs2292474

Variant names:

• chr11-1837342-C-T
• rs2292474
• NM_001394072.1:c.1075C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001394072.1(SYT8):​c.1075C>T​(p.Arg359Trp) variant causes a missense change. The variant allele was found at a frequency of 0.481 in 1,594,152 control chromosomes in the GnomAD database, including 189,039 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R359Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.42 (14671 hom., cov: 35)
  • Exomes 𝑓: 0.49 (174368 hom.)
• Consequence: SYT8 NM_001394072.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.09
• Publications: 24 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]

ENSG00000304059 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.6974954E-5).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

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.1075C>T	p.Arg359Trp	missense	Exon 8 of 8	NP_001381001.1	Q8NBV8-4
	SYT8	NM_001290332.2		c.1120C>T	p.Arg374Trp	missense	Exon 9 of 9	NP_001277261.2
	SYT8	NM_001290333.2		c.1117C>T	p.Arg373Trp	missense	Exon 9 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.1075C>T	p.Arg359Trp	missense	Exon 8 of 8	ENSP00000343691.3	Q8NBV8-4
	SYT8	ENST00000381978.7	TSL:1	c.1111C>T	p.Arg371Trp	missense	Exon 9 of 9	ENSP00000371406.3	H0Y3G9
	SYT8	ENST00000490707.5	TSL:1	n.3355C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63225 AN: 152058 Hom.: 14658 Cov.: 35

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.493

Gnomad OTH AF: 0.399

GnomAD2 exomes AF: 0.477 AC: 105701 AN: 221570 AF XY: 0.486

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.482

Gnomad ASJ exome AF: 0.367

Gnomad EAS exome AF: 0.385

Gnomad FIN exome AF: 0.647

Gnomad NFE exome AF: 0.494

Gnomad OTH exome AF: 0.481

GnomAD4 exome AF: 0.488 AC: 703175 AN: 1441976 Hom.: 174368 Cov.: 73 AF XY: 0.491 AC XY: 352210 AN XY: 717198

African (AFR) AF: 0.200 AC: 6668 AN: 33286

American (AMR) AF: 0.471 AC: 20674 AN: 43880

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 9227 AN: 25850

East Asian (EAS) AF: 0.388 AC: 15309 AN: 39452

South Asian (SAS) AF: 0.557 AC: 47728 AN: 85626

European-Finnish (FIN) AF: 0.637 AC: 25646 AN: 40274

Middle Eastern (MID) AF: 0.442 AC: 2539 AN: 5742

European-Non Finnish (NFE) AF: 0.494 AC: 547805 AN: 1108006

Other (OTH) AF: 0.461 AC: 27579 AN: 59860

GnomAD4 genome AF: 0.416 AC: 63263 AN: 152176 Hom.: 14671 Cov.: 35 AF XY: 0.426 AC XY: 31661 AN XY: 74400

African (AFR) AF: 0.209 AC: 8669 AN: 41542

American (AMR) AF: 0.446 AC: 6830 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1248 AN: 3472

East Asian (EAS) AF: 0.380 AC: 1961 AN: 5162

South Asian (SAS) AF: 0.555 AC: 2679 AN: 4826

European-Finnish (FIN) AF: 0.647 AC: 6857 AN: 10604

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.493 AC: 33505 AN: 67952

Other (OTH) AF: 0.401 AC: 847 AN: 2112

Alfa AF: 0.456 Hom.: 3526

Bravo AF: 0.390

TwinsUK AF: 0.482 AC: 1788

ALSPAC AF: 0.495 AC: 1907

ESP6500AA AF: 0.208 AC: 906

ESP6500EA AF: 0.481 AC: 4072

ExAC AF: 0.467 AC: 55475

Asia WGS AF: 0.434 AC: 1506 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.021
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.042	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.000037	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-3.7	N
PhyloP100		4.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	13	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.076
ClinPred		0.0059	T
GERP RS		2.7
Varity_R		0.068
gMVP		0.64
Mutation Taster		=98/2	polymorphism (auto)

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: rs2292474; hg19: chr11-1858572; COSMIC: COSV53289762; COSMIC: COSV53289762;