11-17736108-TG-T

Position:

• chr11-17736108-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001112741.2(KCNC1):​c.108del​(p.Trp36CysfsTer33) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNC1 NM_001112741.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.82

Genes affected

KCNC1 (HGNC:6233): (potassium voltage-gated channel subfamily C member 1) This gene encodes a member of a family of integral membrane proteins that mediate the voltage-dependent potassium ion permeability of excitable membranes. Alternative splicing is thought to result in two transcript variants encoding isoforms that differ at their C-termini. These isoforms have had conflicting names in the literature: the longer isoform has been called both "b" and "alpha", while the shorter isoform has been called both "a" and "beta" (PMIDs 1432046, 12091563). [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-17736108-TG-T is Pathogenic according to our data. Variant chr11-17736108-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 658535.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNC1	NM_001112741.2	c.108del	p.Trp36CysfsTer33	frameshift_variant	1/4	ENST00000265969.8
KCNC1	NM_004976.4	c.108del	p.Trp36CysfsTer33	frameshift_variant	1/2
KCNC1	XM_047426916.1	c.108del	p.Trp36CysfsTer33	frameshift_variant	1/4
KCNC1	XR_930866.3	n.1330del		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNC1	ENST00000265969.8	c.108del	p.Trp36CysfsTer33	frameshift_variant	1/4	5	NM_001112741.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive myoclonic epilepsy type 7 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 08, 2018

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in KCNC1 cause disease. This variant has not been reported in the literature in individuals with KCNC1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp36Cysfs*33) in the KCNC1 gene. It is expected to result in an absent or disrupted protein product. This variant disrupts a region of the protein in which other variant(s) (p.Thr231Ala, p.Arg320His, p.Arg339*) have been observed in affected individuals (PMID: 25401298, 28380698, 28145425, Invitae). This suggests that this may be a clinically significant region of the KCNC1 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1590088831; hg19: chr11-17757655;