dbSNP rs1555781806: KCNC3:p.Ser4CysfsTer96 (chr19-50329070-CTG-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPP5_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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.17

Publications

0 publications found

Variant links:

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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Orphanet

KCNC3 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_004977.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNC3	NM_004977.3	MANE Select	c.11_12delCA	p.Ser4CysfsTer96	frameshift	Exon 1 of 5	NP_004968.2
KCNC3	NM_001372305.1		c.-218_-217delCA		5_prime_UTR	Exon 1 of 5	NP_001359234.1
KCNC3	NM_001372305.1		c.-218_-217delCA		non_coding_transcript	N/A	NP_001359234.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNC3	ENST00000477616.2	TSL:1 MANE Select	c.11_12delCA	p.Ser4CysfsTer96	frameshift	Exon 1 of 5	ENSP00000434241.1	Q14003
KCNC3	ENST00000670667.1		c.11_12delCA	p.Ser4CysfsTer96	frameshift	Exon 1 of 4	ENSP00000499301.1	A0A590UJ62
KCNC3	ENST00000376959.6	TSL:5	c.11_12delCA	p.Ser4CysfsTer96	frameshift	Exon 1 of 5	ENSP00000366158.2	E7ETH1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000182

AC:

AN:

1096650

Hom.:

AF XY:

0.00

AC XY:

AN XY:

538260

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22600

American (AMR)

AF:

0.00

AC:

AN:

16672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18436

East Asian (EAS)

AF:

0.00

AC:

AN:

25074

South Asian (SAS)

AF:

0.00

AC:

AN:

46614

European-Finnish (FIN)

AF:

0.0000804

AC:

AN:

24884

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3068

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

894950

Other (OTH)

AF:

0.00

AC:

AN:

44352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Spinocerebellar ataxia type 13 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.2

Mutation Taster

=28/172

disease causing (ClinVar)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over