rs1305901422

Variant names:

• chr19-50323962-C-G
• rs1305901422
• NM_004977.3:c.991G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-50323962-C-G
• chr19-50323962-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004977.3(KCNC3):​c.991G>C​(p.Gly331Arg) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.47
• Publications: 0 publications found

Genes affected

KCNC3 (HGNC:6235): (potassium voltage-gated channel subfamily C member 3) The Shaker gene family of Drosophila encodes components of voltage-gated potassium channels and is comprised of four subfamilies. Based on sequence similarity, this gene is similar to one of these subfamilies, namely the Shaw subfamily. The protein encoded by this gene belongs to the delayed rectifier class of channel proteins and is an integral membrane protein that mediates the voltage-dependent potassium ion permeability of excitable membranes. Alternate splicing results in several transcript variants. [provided by RefSeq, Mar 2014]

KCNC3 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 13

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.991G>C	p.Gly331Arg	missense_variant	Exon 2 of 5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.763G>C	p.Gly255Arg	missense_variant	Exon 2 of 5		NP_001359234.1
KCNC3	NR_110912.2	n.69-3178G>C		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.991G>C	p.Gly331Arg	missense_variant	Exon 2 of 5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.991G>C	p.Gly331Arg	missense_variant	Exon 2 of 4			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.991G>C	p.Gly331Arg	missense_variant	Exon 2 of 5	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.-74-3178G>C		intron_variant	Intron 1 of 3	2		ENSP00000432438.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;D
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	0.34	.;N
PhyloP100		2.5
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.042	D;D
Polyphen		0.11	.;B
Vest4		0.61
MutPred		0.34		Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);
MVP		0.93
ClinPred		0.72	D
GERP RS		2.7
Varity_R		0.12
gMVP		0.46
Mutation Taster		=98/2	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: rs1305901422; hg19: chr19-50827219;