rs104894699

Positions:

• chr19-50323694-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_004977.3(KCNC3):​c.1259G>A​(p.Arg420His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R420R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.76

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004977.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 19-50323694-C-T is Pathogenic according to our data. Variant chr19-50323694-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50323694-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNC3	NM_004977.3	c.1259G>A	p.Arg420His	missense_variant	2/5	ENST00000477616.2
KCNC3	NM_001372305.1	c.1031G>A	p.Arg344His	missense_variant	2/5
KCNC3	NR_110912.2	n.69-2910G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNC3	ENST00000477616.2	c.1259G>A	p.Arg420His	missense_variant	2/5	1	NM_004977.3
KCNC3	ENST00000670667.1	c.1259G>A	p.Arg420His	missense_variant	2/4			P3
KCNC3	ENST00000376959.6	c.1259G>A	p.Arg420His	missense_variant	2/5	5		A2
KCNC3	ENST00000474951.1	c.-74-2910G>A		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia type 13 Pathogenic:8

Pathogenic, no assertion criteria provided	research	O&I group, Department of Genetics, University Medical Center of Groningen	Jul 22, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2006	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Aug 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16501573). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.76). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013473). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 08, 2016	- -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2022	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change alters KCNC3 gene expression (PMID: 16501573). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNC3 protein function. ClinVar contains an entry for this variant (Variation ID: 13473). This missense change has been observed in individual(s) with autosomal dominant spinocerebellar ataxia (PMID: 16501573). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 420 of the KCNC3 protein (p.Arg420His). -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 28, 2018	Not found in the total gnomAD dataset, and the data is high quality (0/282352 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease in affected and unaffected individuals, but from a single family. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	.;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.92		Gain of methylation at R417 (P = 0.0626);Gain of methylation at R417 (P = 0.0626);
MVP		0.98
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.91
gMVP		0.99

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: rs104894699; hg19: chr19-50826951; COSMIC: COSV65387781;