rs201878910

Variant names:

• chr11-67040175-C-T
• rs201878910
• NM_177963.4:c.593C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_177963.4(SYT12):​c.593C>T​(p.Pro198Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000277 in 1,587,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: SYT12 NM_177963.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88
• Publications: 1 publications found

Genes affected

SYT12 (HGNC:18381): (synaptotagmin 12) This gene is a member of the synaptotagmin gene family and encodes a protein similar to other family members that mediate calcium-dependent regulation of membrane trafficking in synaptic transmission. Studies of the orthologous gene in rat have shown that the encoded protein selectively modulates spontaneous synaptic-vesicle exocytosis and may also be involved in regulating calcium independent secretion in nonneuronal cells. Alternative splicing results in multiple transcript variants. The gene has previously been referred to as synaptotagmin XI but has been renamed synaptotagmin XII to be standard with mouse and rat official nomenclature.[provided by RefSeq, Apr 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177963.4. 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
	SYT12	NM_177963.4	MANE Select	c.593C>T	p.Pro198Leu	missense	Exon 4 of 8	NP_808878.1	Q8IV01
	SYT12	NM_001177880.2		c.593C>T	p.Pro198Leu	missense	Exon 4 of 8	NP_001171351.1	Q8IV01
	SYT12	NM_001318773.2		c.248C>T	p.Pro83Leu	missense	Exon 5 of 9	NP_001305702.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT12	ENST00000527043.6	TSL:1 MANE Select	c.593C>T	p.Pro198Leu	missense	Exon 4 of 8	ENSP00000435316.1	Q8IV01
	SYT12	ENST00000393946.6	TSL:2	c.593C>T	p.Pro198Leu	missense	Exon 7 of 11	ENSP00000377520.2	Q8IV01
	SYT12	ENST00000525457.5	TSL:2	c.593C>T	p.Pro198Leu	missense	Exon 4 of 8	ENSP00000431400.1	Q8IV01

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000555 AC: 13 AN: 234154 AF XY: 0.0000875

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: 0.0000982

Gnomad NFE exome AF: 0.0000189

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000272 AC: 39 AN: 1435516 Hom.: 0 Cov.: 31 AF XY: 0.0000366 AC XY: 26 AN XY: 709710

African (AFR) AF: 0.00 AC: 0 AN: 33180

American (AMR) AF: 0.00 AC: 0 AN: 43902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24470

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39276

South Asian (SAS) AF: 0.000243 AC: 20 AN: 82270

European-Finnish (FIN) AF: 0.0000383 AC: 2 AN: 52220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5268

European-Non Finnish (NFE) AF: 0.0000119 AC: 13 AN: 1095752

Other (OTH) AF: 0.0000338 AC: 2 AN: 59178

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000495 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.036	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-9.6	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.84
MPC		0.69
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.74
Mutation Taster		=7/93	disease causing

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: rs201878910; hg19: chr11-66807646; COSMIC: COSV67354104; COSMIC: COSV67354104;