rs1555781806

Variant names:

• chr19-50329070-CTG-C
• rs1555781806
• NM_004977.3:c.11_12delCA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_004977.3(KCNC3):​c.11_12delCA​(p.Ser4CysfsTer96) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNC3 NM_004977.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.17
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PP5: Variant 19-50329070-CTG-C is Pathogenic according to our data. Variant chr19-50329070-CTG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 522615.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.11_12delCA	p.Ser4CysfsTer96	frameshift_variant	Exon 1 of 5	ENST00000477616.2	NP_004968.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.11_12delCA	p.Ser4CysfsTer96	frameshift_variant	Exon 1 of 5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.11_12delCA	p.Ser4CysfsTer96	frameshift_variant	Exon 1 of 4			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.11_12delCA	p.Ser4CysfsTer96	frameshift_variant	Exon 1 of 5	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.-75+4397_-75+4398delCA		intron_variant	Intron 1 of 3	2		ENSP00000432438.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000182 AC: 2 AN: 1096650 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 538260

African (AFR) AF: 0.00 AC: 0 AN: 22600

American (AMR) AF: 0.00 AC: 0 AN: 16672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18436

East Asian (EAS) AF: 0.00 AC: 0 AN: 25074

South Asian (SAS) AF: 0.00 AC: 0 AN: 46614

European-Finnish (FIN) AF: 0.0000804 AC: 2 AN: 24884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3068

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 894950

Other (OTH) AF: 0.00 AC: 0 AN: 44352

GnomAD4 genome Cov.: 20

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 13 Pathogenic:1

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=28/172	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: rs1555781806; hg19: chr19-50832327;