chr11-67034687-C-T

Variant names:

• chr11-67034687-C-T
• rs867942323
• NM_177963.4:c.77C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_177963.4(SYT12):​c.77C>T​(p.Ala26Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. A26S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SYT12 NM_177963.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11212617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYT12	NM_177963.4	c.77C>T	p.Ala26Val	missense_variant	Exon 3 of 8	ENST00000527043.6	NP_808878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYT12	ENST00000527043.6	c.77C>T	p.Ala26Val	missense_variant	Exon 3 of 8	1	NM_177963.4	ENSP00000435316.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450250 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 721454

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.77C>T (p.A26V) alteration is located in exon 3 (coding exon 2) of the SYT12 gene. This alteration results from a C to T substitution at nucleotide position 77, causing the alanine (A) at amino acid position 26 to be replaced by a valine (V). 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	0.092
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T;T;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.86	.;.;D;D
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.20	N;N;N;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.0	N;N;N;N
REVEL	Benign	0.077
Sift	Benign	0.15	T;T;T;T
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.010	B;B;B;.
Vest4		0.26
MutPred		0.27		Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);
MVP		0.092
MPC		0.16
ClinPred		0.61	D
GERP RS		4.9
Varity_R		0.12
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs867942323; hg19: chr11-66802158;