NM_177963.4:c.619C>T

Variant names:

• chr11-67040201-C-T
• rs750021799
• NM_177963.4:c.619C>T

Variant summary

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

The NM_177963.4(SYT12):​c.619C>T​(p.Arg207Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000191 in 1,570,526 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: SYT12 NM_177963.4 missense, splice_region
• Scores: Splicing: ADA: 0.004352
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.742
• Publications: 0 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 0 ACMG points.

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.619C>T	p.Arg207Trp	missense splice_region	Exon 4 of 8	NP_808878.1	Q8IV01
	SYT12	NM_001177880.2		c.619C>T	p.Arg207Trp	missense splice_region	Exon 4 of 8	NP_001171351.1	Q8IV01
	SYT12	NM_001318773.2		c.274C>T	p.Arg92Trp	missense splice_region	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.619C>T	p.Arg207Trp	missense splice_region	Exon 4 of 8	ENSP00000435316.1	Q8IV01
	SYT12	ENST00000393946.6	TSL:2	c.619C>T	p.Arg207Trp	missense splice_region	Exon 7 of 11	ENSP00000377520.2	Q8IV01
	SYT12	ENST00000525457.5	TSL:2	c.619C>T	p.Arg207Trp	missense splice_region	Exon 4 of 8	ENSP00000431400.1	Q8IV01

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000683 AC: 15 AN: 219764 AF XY: 0.0000600

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000771

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000190 AC: 27 AN: 1418236 Hom.: 0 Cov.: 31 AF XY: 0.0000157 AC XY: 11 AN XY: 698560

African (AFR) AF: 0.00 AC: 0 AN: 33008

American (AMR) AF: 0.00 AC: 0 AN: 43114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23262

East Asian (EAS) AF: 0.000638 AC: 25 AN: 39178

South Asian (SAS) AF: 0.00 AC: 0 AN: 78574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4556

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1086680

Other (OTH) AF: 0.0000171 AC: 1 AN: 58532

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74460

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000341 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000993 AC: 12

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	Uncertain	0.36
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.74
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.69		Gain of catalytic residue at Q209 (P = 0.1323)
MVP		0.81
MPC		0.68
ClinPred		0.55	D
GERP RS		2.6
Varity_R		0.86
gMVP		0.70
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0044
dbscSNV1_RF	Benign	0.11
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: rs750021799; hg19: chr11-66807672; COSMIC: COSV67353457; COSMIC: COSV67353457;