11-1835109-G-T

Position:

• chr11-1835109-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394072.1(SYT8):​c.4G>T​(p.Gly2Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SYT8 NM_001394072.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0860

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]

SYT8 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17663172).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYT8	NM_001394072.1	c.4G>T	p.Gly2Trp	missense_variant	1/8	ENST00000341958.4	NP_001381001.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYT8	ENST00000341958.4	c.4G>T	p.Gly2Trp	missense_variant	1/8	5	NM_001394072.1	ENSP00000343691.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2024

The c.46G>T (p.G16W) alteration is located in exon 2 (coding exon 2) of the SYT8 gene. This alteration results from a G to T substitution at nucleotide position 46, causing the glycine (G) at amino acid position 16 to be replaced by a tryptophan (W). 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	Benign	0.21
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Uncertain	0.97
DEOGEN2	Benign	0.019	.;.;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.33	T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.6	.;.;L;.
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-5.2	D;D;N;D
REVEL	Benign	0.066
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.99	.;.;D;D
Vest4		0.23, 0.22
MutPred		0.45		.;.;Loss of disorder (P = 0.0246);.;
MVP		0.49
MPC		0.46
ClinPred		0.96	D
GERP RS		0.81
Varity_R		0.15
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1192796251; hg19: chr11-1856339;