chr11-17736073-C-G

Variant names:

• chr11-17736073-C-G
• NM_001112741.2:c.71C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001112741.2(KCNC1):​c.71C>G​(p.Ser24Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S24S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNC1 NM_001112741.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.26
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

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.71C>G	p.Ser24Trp	missense	Exon 1 of 4	NP_001106212.1	P48547-2
	KCNC1	NM_004976.4		c.71C>G	p.Ser24Trp	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.71C>G	p.Ser24Trp	missense	Exon 1 of 4	ENSP00000265969.7	P48547-2
	KCNC1	ENST00000379472.4	TSL:1	c.71C>G	p.Ser24Trp	missense	Exon 1 of 2	ENSP00000368785.3	P48547-1
	KCNC1	ENST00000639325.2	TSL:5	c.71C>G	p.Ser24Trp	missense	Exon 1 of 5	ENSP00000492663.2	A0A1W2PNZ3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447996 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719174

African (AFR) AF: 0.00 AC: 0 AN: 33150

American (AMR) AF: 0.00 AC: 0 AN: 43738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25510

East Asian (EAS) AF: 0.00 AC: 0 AN: 39178

South Asian (SAS) AF: 0.00 AC: 0 AN: 84296

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105744

Other (OTH) AF: 0.00 AC: 0 AN: 59768

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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Benign	0.38	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.54		Loss of disorder (P = 0.0046)
MVP		0.91
MPC		3.2
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.74
gMVP		0.99
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

hg19: chr11-17757620;