NM_177963.4:c.577C>A

Variant names:

• chr11-67040159-C-A
• rs374157812
• NM_177963.4:c.577C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_177963.4(SYT12):​c.577C>A​(p.Arg193Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000104 in 1,447,278 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R193C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SYT12 NM_177963.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.28
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

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.577C>A	p.Arg193Ser	missense	Exon 4 of 8	NP_808878.1	Q8IV01
	SYT12	NM_001177880.2		c.577C>A	p.Arg193Ser	missense	Exon 4 of 8	NP_001171351.1	Q8IV01
	SYT12	NM_001318773.2		c.232C>A	p.Arg78Ser	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.577C>A	p.Arg193Ser	missense	Exon 4 of 8	ENSP00000435316.1	Q8IV01
	SYT12	ENST00000393946.6	TSL:2	c.577C>A	p.Arg193Ser	missense	Exon 7 of 11	ENSP00000377520.2	Q8IV01
	SYT12	ENST00000525457.5	TSL:2	c.577C>A	p.Arg193Ser	missense	Exon 4 of 8	ENSP00000431400.1	Q8IV01

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000824 AC: 2 AN: 242750 AF XY: 0.0000153

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000913

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000104 AC: 15 AN: 1447278 Hom.: 0 Cov.: 31 AF XY: 0.00000697 AC XY: 5 AN XY: 717482

African (AFR) AF: 0.00 AC: 0 AN: 33292

American (AMR) AF: 0.00 AC: 0 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25318

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39408

South Asian (SAS) AF: 0.00 AC: 0 AN: 84570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52720

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5524

European-Non Finnish (NFE) AF: 0.0000127 AC: 14 AN: 1102498

Other (OTH) AF: 0.00 AC: 0 AN: 59686

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

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	0.86
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	2.0	M
PhyloP100		6.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.014	D
Polyphen		0.93	P
Vest4		0.78
MutPred		0.78		Gain of phosphorylation at R193 (P = 0.0915)
MVP		0.81
MPC		0.65
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.88
gMVP		0.76
Mutation Taster		=63/37	polymorphism

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: rs374157812; hg19: chr11-66807630;