15-54013117-A-C

Variant names:

• chr15-54013117-A-C
• rs370228589
• NM_001080534.3:c.214A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080534.3(UNC13C):​c.214A>C​(p.Thr72Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T72S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UNC13C NM_001080534.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.218
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.072935164).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080534.3. 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
	UNC13C	NM_001080534.3	MANE Select	c.214A>C	p.Thr72Pro	missense	Exon 2 of 33	NP_001074003.1	Q8NB66
	UNC13C	NM_001329919.2		c.214A>C	p.Thr72Pro	missense	Exon 2 of 32	NP_001316848.1	A0A3B3ISZ1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13C	ENST00000260323.16	TSL:5 MANE Select	c.214A>C	p.Thr72Pro	missense	Exon 2 of 33	ENSP00000260323.11	Q8NB66
	UNC13C	ENST00000647821.1		c.214A>C	p.Thr72Pro	missense	Exon 2 of 32	ENSP00000497525.1	A0A3B3ISZ1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000330 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	4.4
DANN	Benign	0.80
DEOGEN2	Benign	0.061	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.22
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.030	D
Polyphen		0.023	B
Vest4		0.29
MVP		0.43
MPC		0.072
ClinPred		0.11	T
GERP RS		-6.3
Varity_R		0.13
gMVP		0.32

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: rs370228589; hg19: chr15-54305314;