11-45252661-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020826.3(SYT13):c.606G>T(p.Arg202Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000484 in 1,611,202 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (1 hom.)
• Consequence: SYT13 NM_020826.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.507

Genes affected

SYT13 (HGNC:14962): (synaptotagmin 13) This gene encodes a member of the large synaptotagmin protein family. Family members have an extracellular N-terminal transmembrane domain and a cytoplasmic C terminus with two tandem C2 domains (C2A and C2B). Synaptotogmin family members can form homo- and heteromeric complexes with each other. They also have different biochemical properties and developmental profiles, and patterns of tissue distribution. Synaptotagmins function as membrane traffickers in multicellular organisms. Two alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028119206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYT13	NM_020826.3	c.606G>T	p.Arg202Ser	missense_variant	4/6	ENST00000020926.8
SYT13	NM_001247987.2	c.174G>T	p.Arg58Ser	missense_variant	6/8
SYT13	XM_047427338.1	c.174G>T	p.Arg58Ser	missense_variant	4/6
SYT13	XM_047427339.1	c.174G>T	p.Arg58Ser	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYT13	ENST00000020926.8	c.606G>T	p.Arg202Ser	missense_variant	4/6	1	NM_020826.3	P1
SYT13	ENST00000533332.1	c.*623G>T		3_prime_UTR_variant, NMD_transcript_variant	6/8	1
SYT13	ENST00000528101.1	c.486G>T	p.Arg162Ser	missense_variant	4/4	4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000229 AC: 57 AN: 248590 Hom.: 0 AF XY: 0.000208 AC XY: 28 AN XY: 134436

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000467

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000515 AC: 752 AN: 1459006 Hom.: 1 Cov.: 31 AF XY: 0.000481 AC XY: 349 AN XY: 725196

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000660

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74346

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000384 Hom.: 0

Bravo AF: 0.000212

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000273

EpiControl AF: 0.000237

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

Oct 29, 2021

The c.606G>T (p.R202S) alteration is located in exon 4 (coding exon 4) of the SYT13 gene. This alteration results from a G to T substitution at nucleotide position 606, causing the arginine (R) at amino acid position 202 to be replaced by a serine (S). 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	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	13
Dann	Benign	0.81
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.046
Sift	Benign	0.21	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.40		Gain of disorder (P = 0.0515);
MVP		0.30
MPC		0.25
ClinPred		0.026	T
GERP RS		2.8
Varity_R		0.14
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs149737973; hg19: chr11-45274212;