19-50323685-C-T

Variant names:

• chr19-50323685-C-T
• rs797044872
• NM_004977.3:c.1268G>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004977.3(KCNC3):​c.1268G>A​(p.Arg423His) 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000244122: "The p.R423H alteration has been shown in multiple independent studies to negatively affect Kv3.3 channel functioning by suppressing current amplitude (Figueroa, 2010), significantly altering gating (Minassian, 2012), or resulting in altered glycosylation and aberrant retention of the mutant channels in the anterograde and/or endosomal vesicles instead of at the plasma membrane (Khare, 2017)."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R423C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21
• Conservation: PhyloP100: 7.76
• Publications: 38 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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000244122: "The p.R423H alteration has been shown in multiple independent studies to negatively affect Kv3.3 channel functioning by suppressing current amplitude (Figueroa, 2010), significantly altering gating (Minassian, 2012), or resulting in altered glycosylation and aberrant retention of the mutant channels in the anterograde and/or endosomal vesicles instead of at the plasma membrane (Khare, 2017)."; SCV000330001: Published functional studies demonstrate a damaging effect, resulting in loss of channel activity consistent with a strong dominant negative effect (Figueroa et al., 2010; Duarri et al., 2015); SCV001378390: Experimental studies have shown that this missense change affects KCNC3 function (PMID: 19953606, 22289912, 25756792, 28467418).; SCV002064519: Functional studies show p.Arg423His disrupts the channel activity of the KCNC3 protein and demonstrates a dominant-negative effect (PMIDs: 19953606, 25756792, 28467418).; SCV002503864: A zebrafish model of the variant recapitulates the cerebellar degeneration, and demonstrated differential affects on Purkinje cell excitability, maturation, and viability to an adult-onset associated variant (PMID: 32644043).; SCV002521695: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19953606, 22289912, 25756792, 28467418).; SCV002557660: "This variant has moderate functional evidence supporting abnormal protein function. Targeted expression in zebrafish and drosophila models have demonstrated disrupted axonal pathfinding and neurodegeneration consistent with the neurodevelopmental presentations of disease in patients (PMIDs: 21543613, 30862666, 28467418). In addition, patch clamp studies of this variant expressed in Xenopus oocytes have shown significant loss of Kv3.3 channel activity, reduced current amplitude and cell surface expression. (PMIDs: 19953606, 22289912, 25756792)."; SCV004176433: Functional studies show p.Arg423His disrupts the channel activity of the KCNC3 protein and demonstrates a dominant-negative effect (Figueroa KP, et. al., 2010).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_004977.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-50323686-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3251038.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 19-50323685-C-T is Pathogenic according to our data. Variant chr19-50323685-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 208671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004977.3. 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
	KCNC3	NM_004977.3	MANE Select	c.1268G>A	p.Arg423His	missense	Exon 2 of 5	NP_004968.2
	KCNC3	NM_001372305.1		c.1040G>A	p.Arg347His	missense	Exon 2 of 5	NP_001359234.1
	KCNC3	NR_110912.2		n.69-2901G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC3	ENST00000477616.2	TSL:1 MANE Select	c.1268G>A	p.Arg423His	missense	Exon 2 of 5	ENSP00000434241.1	Q14003
	KCNC3	ENST00000670667.1		c.1268G>A	p.Arg423His	missense	Exon 2 of 4	ENSP00000499301.1	A0A590UJ62
	KCNC3	ENST00000376959.6	TSL:5	c.1268G>A	p.Arg423His	missense	Exon 2 of 5	ENSP00000366158.2	E7ETH1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000536 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Spinocerebellar ataxia type 13 (11)
9	-	-	not provided (9)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.93		Loss of methylation at R423 (P = 0.0754)
MVP		0.99
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.89
gMVP		0.99
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs797044872; hg19: chr19-50826942;