chr11-17736070-G-A

Variant names:

• chr11-17736070-G-A
• rs1158193192
• NM_001112741.2:c.68G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• progressive myoclonic epilepsy type 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• progressive myoclonus epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001112741.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC1	NM_001112741.2	MANE Select	c.68G>A	p.Arg23His	missense	Exon 1 of 4	NP_001106212.1	P48547-2
	KCNC1	NM_004976.4		c.68G>A	p.Arg23His	missense	Exon 1 of 2	NP_004967.1	P48547-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC1	ENST00000265969.8	TSL:5 MANE Select	c.68G>A	p.Arg23His	missense	Exon 1 of 4	ENSP00000265969.7	P48547-2
	KCNC1	ENST00000379472.4	TSL:1	c.68G>A	p.Arg23His	missense	Exon 1 of 2	ENSP00000368785.3	P48547-1
	KCNC1	ENST00000639325.2	TSL:5	c.68G>A	p.Arg23His	missense	Exon 1 of 5	ENSP00000492663.2	A0A1W2PNZ3

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

African (AFR) AF: 0.00 AC: 0 AN: 33098

American (AMR) AF: 0.00 AC: 0 AN: 43572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25394

East Asian (EAS) AF: 0.00 AC: 0 AN: 39142

South Asian (SAS) AF: 0.00 AC: 0 AN: 83910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104764

Other (OTH) AF: 0.00 AC: 0 AN: 59706

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Progressive myoclonic epilepsy type 7 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.70
Sift	Benign	0.12	T
Sift4G	Benign	0.26	T
Polyphen		1.0	D
Vest4		0.27
MutPred		0.58		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
Mutation Taster		=53/47	polymorphism

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: rs1158193192; hg19: chr11-17757617;