chr15-54013688-A-G

Position:

• chr15-54013688-A-G

Variant summary

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

The NM_001080534.3(UNC13C):​c.785A>G​(p.Glu262Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UNC13C NM_001080534.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.25

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	Protein	UniProt
UNC13C	NM_001080534.3	c.785A>G	p.Glu262Gly	missense_variant	2/33	ENST00000260323.16	NP_001074003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC13C	ENST00000260323.16	c.785A>G	p.Glu262Gly	missense_variant	2/33	5	NM_001080534.3	ENSP00000260323	A1
UNC13C	ENST00000647821.1	c.785A>G	p.Glu262Gly	missense_variant	2/32			ENSP00000497525	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Apr 29, 2024

The c.785A>G (p.E262G) alteration is located in exon 1 (coding exon 1) of the UNC13C gene. This alteration results from a A to G substitution at nucleotide position 785, causing the glutamic acid (E) at amino acid position 262 to be replaced by a glycine (G). 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	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.97	.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.6	.;N
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.032	.;D
Polyphen		1.0	.;D
Vest4		0.79
MutPred		0.18		Gain of catalytic residue at E262 (P = 0.0217);Gain of catalytic residue at E262 (P = 0.0217);
MVP		0.96
MPC		0.31
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.23
gMVP		0.84

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: chr15-54305885;