11-17736017-C-G

Variant names:

• chr11-17736017-C-G
• rs1487238241
• NM_001112741.2:c.15C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001112741.2(KCNC1):​c.15C>G​(p.Asp5Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000295 in 1,356,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D5D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: KCNC1 NM_001112741.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.19
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071395695).

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.15C>G	p.Asp5Glu	missense	Exon 1 of 4	NP_001106212.1	P48547-2
	KCNC1	NM_004976.4		c.15C>G	p.Asp5Glu	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.15C>G	p.Asp5Glu	missense	Exon 1 of 4	ENSP00000265969.7	P48547-2
	KCNC1	ENST00000379472.4	TSL:1	c.15C>G	p.Asp5Glu	missense	Exon 1 of 2	ENSP00000368785.3	P48547-1
	KCNC1	ENST00000639325.2	TSL:5	c.15C>G	p.Asp5Glu	missense	Exon 1 of 5	ENSP00000492663.2	A0A1W2PNZ3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000771 AC: 1 AN: 129752 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000295 AC: 4 AN: 1356250 Hom.: 0 Cov.: 31 AF XY: 0.00000301 AC XY: 2 AN XY: 664630

African (AFR) AF: 0.00 AC: 0 AN: 30612

American (AMR) AF: 0.00 AC: 0 AN: 33290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21672

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 72254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5282

European-Non Finnish (NFE) AF: 0.00000377 AC: 4 AN: 1062414

Other (OTH) AF: 0.00 AC: 0 AN: 56290

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	0.0095	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	-0.20	N
PhyloP100		2.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.30
Sift	Benign	0.53	T
Sift4G	Benign	0.30	T
Polyphen		0.012	B
Vest4		0.075
MutPred		0.24		Gain of disorder (P = 0.0766)
MVP		0.71
MPC		1.4
ClinPred		0.21	T
GERP RS		3.3
Varity_R		0.092
gMVP		0.84
Mutation Taster		=64/36	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: rs1487238241; hg19: chr11-17757564;