15-54013815-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001080534.3(UNC13C):c.912C>G(p.Asp304Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00631 in 1,612,176 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0045 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (66 hom.)
• Consequence: UNC13C NM_001080534.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.40

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008742541).
• BP6: Variant 15-54013815-C-G is Benign according to our data. Variant chr15-54013815-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2645361.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13C	NM_001080534.3	c.912C>G	p.Asp304Glu	missense_variant	2/33	ENST00000260323.16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13C	ENST00000260323.16	c.912C>G	p.Asp304Glu	missense_variant	2/33	5	NM_001080534.3	A1
UNC13C	ENST00000647821.1	c.912C>G	p.Asp304Glu	missense_variant	2/32			P4

Frequencies

GnomAD3 genomes AF: 0.00452 AC: 687 AN: 152090 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0438

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00602

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00573

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00622 AC: 1538 AN: 247140 Hom.: 21 AF XY: 0.00660 AC XY: 886 AN XY: 134184

Gnomad AFR exome AF: 0.000972

Gnomad AMR exome AF: 0.00364

Gnomad ASJ exome AF: 0.0421

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.00561

Gnomad FIN exome AF: 0.00112

Gnomad NFE exome AF: 0.00667

Gnomad OTH exome AF: 0.00724

GnomAD4 exome AF: 0.00650 AC: 9486 AN: 1459968 Hom.: 66 Cov.: 31 AF XY: 0.00671 AC XY: 4877 AN XY: 726364

Gnomad4 AFR exome AF: 0.000961

Gnomad4 AMR exome AF: 0.00390

Gnomad4 ASJ exome AF: 0.0453

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00581

Gnomad4 FIN exome AF: 0.00165

Gnomad4 NFE exome AF: 0.00632

Gnomad4 OTH exome AF: 0.00757

GnomAD4 genome AF: 0.00451 AC: 686 AN: 152208 Hom.: 5 Cov.: 32 AF XY: 0.00431 AC XY: 321 AN XY: 74436

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.0438

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00603

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00573

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00927 Hom.: 13

Bravo AF: 0.00515

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00209 AC: 8

ESP6500EA AF: 0.00835 AC: 69

ExAC AF: 0.00568 AC: 686

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00900

EpiControl AF: 0.00842

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

UNC13C: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	0.13
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0087	T;T
MetaSVM	Uncertain	-0.27	T
MutationTaster	Benign	0.88	D;D;D
PrimateAI	Pathogenic	0.81	D
Polyphen		1.0	.;D
Vest4		0.65
MutPred		0.16		Gain of MoRF binding (P = 0.1207);Gain of MoRF binding (P = 0.1207);
MVP		0.91
MPC		0.28
ClinPred		0.022	T
GERP RS		2.1
Varity_R		0.097
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs149448818; hg19: chr15-54306012;