rs104894700

Variant names:

• chr19-50323609-G-C
• rs104894700
• NM_004977.3:c.1344C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-50323609-G-C
• chr19-50323609-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1 PM2 PP3_Moderate PP5

The NM_004977.3(KCNC3):​c.1344C>G​(p.Phe448Leu) variant causes a missense change. 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 (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.94
• Publications: 28 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: Likely_pathogenic. The variant received 9 ACMG points.

• PS1: Transcript NM_004977.3 (KCNC3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• PP5: Variant 19-50323609-G-C is Pathogenic according to our data. Variant chr19-50323609-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 545048.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.1344C>G	p.Phe448Leu	missense_variant	Exon 2 of 5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.1116C>G	p.Phe372Leu	missense_variant	Exon 2 of 5		NP_001359234.1
KCNC3	NR_110912.2	n.69-2825C>G		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.1344C>G	p.Phe448Leu	missense_variant	Exon 2 of 5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.1344C>G	p.Phe448Leu	missense_variant	Exon 2 of 4			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.1344C>G	p.Phe448Leu	missense_variant	Exon 2 of 5	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.-74-2825C>G		intron_variant	Intron 1 of 3	2		ENSP00000432438.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1

Nov 03, 2016

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Benign	0.83
DEOGEN2	Uncertain	0.54	D;D
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	-0.17	.;N
PhyloP100		4.9
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.70
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.088	B;D
Vest4		0.78
MutPred		0.82		Gain of disorder (P = 0.3501);Gain of disorder (P = 0.3501);
MVP		0.97
ClinPred		0.77	D
GERP RS		0.99
Varity_R		0.40
gMVP		0.92
Mutation Taster		=11/89	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: rs104894700; hg19: chr19-50826866;