chr11-17771777-G-C

Position:

• chr11-17771777-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001112741.2(KCNC1):​c.683G>C​(p.Arg228Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R228L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNC1 NM_001112741.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.95

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]

KCNC1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNC1. . Gene score misZ 4.5189 (greater than the threshold 3.09). Trascript score misZ 5.1707 (greater than threshold 3.09). GenCC has associacion of gene with progressive myoclonic epilepsy type 7, progressive myoclonus epilepsy, complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29365695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNC1	NM_001112741.2	c.683G>C	p.Arg228Pro	missense_variant	2/4	ENST00000265969.8	NP_001106212.1
KCNC1	NM_004976.4	c.683G>C	p.Arg228Pro	missense_variant	2/2		NP_004967.1
KCNC1	XM_047426916.1	c.683G>C	p.Arg228Pro	missense_variant	2/4		XP_047282872.1
KCNC1	XR_930866.3	n.1905G>C		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNC1	ENST00000265969.8	c.683G>C	p.Arg228Pro	missense_variant	2/4	5	NM_001112741.2	ENSP00000265969.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251490 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2017

The p.R228P variant (also known as c.683G>C), located in coding exon 2 of the KCNC1 gene, results from a G to C substitution at nucleotide position 683. The arginine at codon 228 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Progressive myoclonic epilepsy type 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 13, 2022

This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 228 of the KCNC1 protein (p.Arg228Pro). This variant has not been reported in the literature in individuals affected with KCNC1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNC1 protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	-0.040	T
MutationAssessor	Benign	0.52	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.60	N;N
REVEL	Uncertain	0.55
Sift	Benign	0.28	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.53	P;.
Vest4		0.32
MutPred		0.48		Loss of catalytic residue at R228 (P = 0.0504);Loss of catalytic residue at R228 (P = 0.0504);
MVP		0.92
MPC		2.1
ClinPred		0.29	T
GERP RS		3.8
Varity_R		0.15
gMVP		0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs200873319; hg19: chr11-17793324;