chr19-17606229-C-G

Variant names:

• chr19-17606229-C-G
• rs1417486551
• NM_001080421.3:c.4937G>C

Variant summary

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

The NM_001080421.3(UNC13A):​c.4937G>C​(p.Arg1646Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R1646H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: UNC13A NM_001080421.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.861
• Publications: 0 publications found

Genes affected

UNC13A (HGNC:23150): (unc-13 homolog A) This gene encodes a member of the UNC13 family. UNC13 proteins bind to phorbol esters and diacylglycerol and play important roles in neurotransmitter release at synapses. Single nucleotide polymorphisms in this gene may be associated with sporadic amyotrophic lateral sclerosis. [provided by RefSeq, Feb 2012]

UNC13A Gene-Disease associations (from GenCC):

• congenital nervous system disorder

  Inheritance: Unknown Classification: LIMITED Submitted by: Illumina, ClinGen

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=0.22559574).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080421.3. 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
	UNC13A	NM_001080421.3	MANE Select	c.4937G>C	p.Arg1646Pro	missense	Exon 44 of 44	NP_001073890.2	Q9UPW8
	UNC13A	NM_001387021.1		c.4925G>C	p.Arg1642Pro	missense	Exon 42 of 42	NP_001373950.1
	UNC13A	NM_001387022.1		c.4922G>C	p.Arg1641Pro	missense	Exon 42 of 42	NP_001373951.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13A	ENST00000519716.7	TSL:5 MANE Select	c.4937G>C	p.Arg1646Pro	missense	Exon 44 of 44	ENSP00000429562.2	Q9UPW8
	UNC13A	ENST00000551649.5	TSL:5	c.4994G>C	p.Arg1665Pro	missense	Exon 45 of 45	ENSP00000447236.1	F8W059
	UNC13A	ENST00000552293.5	TSL:5	c.4919G>C	p.Arg1640Pro	missense	Exon 42 of 42	ENSP00000447572.1	F8W0P6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398756 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 690542

African (AFR) AF: 0.00 AC: 0 AN: 30776

American (AMR) AF: 0.00 AC: 0 AN: 36108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25124

East Asian (EAS) AF: 0.00 AC: 0 AN: 35418

South Asian (SAS) AF: 0.00 AC: 0 AN: 79520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5576

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1080574

Other (OTH) AF: 0.00 AC: 0 AN: 57968

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.034
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.86
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.15
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.034	D
Polyphen		0.85	P
Vest4		0.43
MutPred		0.55		Loss of solvent accessibility (P = 0.0364)
MVP		0.11
MPC		1.7
ClinPred		0.93	D
GERP RS		3.0
Varity_R		0.69
gMVP		0.78
Mutation Taster		=74/26	polymorphism

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: rs1417486551; hg19: chr19-17717038;