chr11-17771795-G-A

Variant names:

• chr11-17771795-G-A
• rs763794003
• NM_001112741.2:c.701G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001112741.2(KCNC1):​c.701G>A​(p.Arg234His) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,882 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. R234C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: KCNC1 NM_001112741.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
• progressive myoclonus epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17211697).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000103 (15/1461882) while in subpopulation EAS AF = 0.000277 (11/39700). AF 95% confidence interval is 0.000155. There are 0 homozygotes in GnomAdExome4. There are 7 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 15 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC1	NM_001112741.2	MANE Select	c.701G>A	p.Arg234His	missense	Exon 2 of 4	NP_001106212.1
	KCNC1	NM_004976.4		c.701G>A	p.Arg234His	missense	Exon 2 of 2	NP_004967.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC1	ENST00000265969.8	TSL:5 MANE Select	c.701G>A	p.Arg234His	missense	Exon 2 of 4	ENSP00000265969.7
	KCNC1	ENST00000379472.4	TSL:1	c.701G>A	p.Arg234His	missense	Exon 2 of 2	ENSP00000368785.3
	KCNC1	ENST00000639325.2	TSL:5	c.701G>A	p.Arg234His	missense	Exon 2 of 5	ENSP00000492663.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251484 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: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

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	Benign	0.081
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.57	N
PhyloP100		4.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.27	N
REVEL	Uncertain	0.32
Sift	Benign	0.16	T
Sift4G	Benign	0.16	T
Polyphen		0.039	B
Vest4		0.098
MutPred		0.48		Gain of glycosylation at T231 (P = 0.116)
MVP		0.54
MPC		1.7
ClinPred		0.24	T
GERP RS		4.7
PromoterAI		-0.019	Neutral
Varity_R		0.055
gMVP		0.65
Mutation Taster		=87/13	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: rs763794003; hg19: chr11-17793342; COSMIC: COSV99789015; COSMIC: COSV99789015;