10-46584498-C-G

Variant names:

• chr10-46584498-C-G
• rs199531397
• NM_031912.5:c.826C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_031912.5(SYT15):​c.826C>G​(p.Pro276Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 152,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SYT15 NM_031912.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25
• Publications: 4 publications found

Genes affected

SYT15 (HGNC:17167): (synaptotagmin 15) This gene encodes a member of the Synaptotagmin (Syt) family of membrane trafficking proteins. Members of this family contain a transmembrane region and a C-terminal-type tandem C2 domain. Unlike related family members, the encoded protein may be involved in membrane trafficking in non-neuronal tissues. Two trancript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

SYT15-AS1 (HGNC:56167): (SYT15 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.24235308).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031912.5. 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
	SYT15	NM_031912.5	MANE Select	c.826C>G	p.Pro276Ala	missense	Exon 6 of 8	NP_114118.2
	SYT15	NM_181519.3		c.826C>G	p.Pro276Ala	missense	Exon 6 of 9	NP_852660.1	Q9BQS2-2
	SYT15-AS1	NR_155739.1		n.313-1360G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT15	ENST00000374321.9	TSL:2 MANE Select	c.826C>G	p.Pro276Ala	missense	Exon 6 of 8	ENSP00000363441.4	Q9BQS2-1
	SYT15	ENST00000503753.5	TSL:1	c.826C>G	p.Pro276Ala	missense	Exon 6 of 9	ENSP00000427607.1	Q9BQS2-2
	SYT15	ENST00000374323.8	TSL:2	c.985C>G	p.Pro329Ala	missense	Exon 5 of 7	ENSP00000363443.3

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152102 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000725

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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000126 AC: 31 AN: 246934 AF XY: 0.0000745

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000189

Gnomad OTH exome AF: 0.000498

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000197 AC: 287 AN: 1459764 Hom.: 0 Cov.: 31 AF XY: 0.000193 AC XY: 140 AN XY: 726176

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000599 AC: 2 AN: 33410

American (AMR) AF: 0.000112 AC: 5 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86096

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000240 AC: 267 AN: 1110780

Other (OTH) AF: 0.000182 AC: 11 AN: 60286

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152102 Hom.: 0 Cov.: 35 AF XY: 0.000188 AC XY: 14 AN XY: 74318

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000725 AC: 3 AN: 41358

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000253 Hom.: 0

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	0.076
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.24	T
PhyloP100		3.2
PROVEAN	Uncertain	-3.1	D
Sift	Benign	0.080	T
Sift4G	Benign	0.17	T
Vest4		0.45
gMVP		0.85

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199531397; hg19: chr10-46965119; COSMIC: COSV65431462; COSMIC: COSV65431462;