15-54012908-T-C

Variant summary

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

The NM_001080534.3(UNC13C):c.5T>C(p.Val2Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: UNC13C NM_001080534.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01

Genes affected

UNC13C (HGNC:23149): (unc-13 homolog C) Predicted to enable calmodulin binding activity and syntaxin-1 binding activity. Predicted to be involved in several processes, including glutamatergic synaptic transmission; regulated exocytosis; and synaptic vesicle maturation. Predicted to be located in presynaptic active zone. Predicted to be active in several cellular components, including axon terminus; parallel fiber to Purkinje cell synapse; and presynaptic active zone cytoplasmic component. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13C	NM_001080534.3	c.5T>C	p.Val2Ala	missense_variant	2/33	ENST00000260323.16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13C	ENST00000260323.16	c.5T>C	p.Val2Ala	missense_variant	2/33	5	NM_001080534.3	A1
UNC13C	ENST00000647821.1	c.5T>C	p.Val2Ala	missense_variant	2/32			P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441022 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 715702

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: 9.06e-7

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

The c.5T>C (p.V2A) alteration is located in exon 1 (coding exon 1) of the UNC13C gene. This alteration results from a T to C substitution at nucleotide position 5, causing the valine (V) at amino acid position 2 to be replaced by an alanine (A). 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	0.14
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Uncertain	-0.26	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
Polyphen		0.52	.;P
Vest4		0.73
MutPred		0.27		Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);
MVP		0.82
MPC		0.31
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.11
gMVP		0.36

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-54305105;