chr11-17736070-G-A

Position:

• chr11-17736070-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001112741.2(KCNC1):​c.68G>A​(p.Arg23His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNC1 NM_001112741.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNC1	NM_001112741.2	c.68G>A	p.Arg23His	missense_variant	1/4	ENST00000265969.8
KCNC1	NM_004976.4	c.68G>A	p.Arg23His	missense_variant	1/2
KCNC1	XM_047426916.1	c.68G>A	p.Arg23His	missense_variant	1/4
KCNC1	XR_930866.3	n.1290G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNC1	ENST00000265969.8	c.68G>A	p.Arg23His	missense_variant	1/4	5	NM_001112741.2	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1445744 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 717856

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive myoclonic epilepsy type 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 04, 2022

This variant has not been reported in the literature in individuals affected with KCNC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 23 of the KCNC1 protein (p.Arg23His). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 938579). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.70
Sift	Benign	0.12	T;T
Sift4G	Benign	0.26	T;T
Polyphen		1.0	D;.
Vest4		0.27
MutPred		0.58		Loss of MoRF binding (P = 0.0068);Loss of MoRF binding (P = 0.0068);
MVP		0.78
MPC		3.0
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.37
gMVP		0.97

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: rs1158193192; hg19: chr11-17757617;