NM_001112741.2:c.683G>T

Variant names:

• chr11-17771777-G-T
• rs200873319
• NM_001112741.2:c.683G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001112741.2(KCNC1):​c.683G>T​(p.Arg228Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000297 in 1,614,234 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R228P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: KCNC1 NM_001112741.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.95
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.062164932).
• BP6: Variant 11-17771777-G-T is Benign according to our data. Variant chr11-17771777-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000322 (49/152350) while in subpopulation SAS AF = 0.00145 (7/4830). AF 95% confidence interval is 0.000679. There are 1 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 49 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.683G>T	p.Arg228Leu	missense	Exon 2 of 4	NP_001106212.1
	KCNC1	NM_004976.4		c.683G>T	p.Arg228Leu	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.683G>T	p.Arg228Leu	missense	Exon 2 of 4	ENSP00000265969.7
	KCNC1	ENST00000379472.4	TSL:1	c.683G>T	p.Arg228Leu	missense	Exon 2 of 2	ENSP00000368785.3
	KCNC1	ENST00000639325.2	TSL:5	c.683G>T	p.Arg228Leu	missense	Exon 2 of 5	ENSP00000492663.2

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152232 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000314 AC: 79 AN: 251490 AF XY: 0.000309

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000295 AC: 431 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.000290 AC XY: 211 AN XY: 727242

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000417 AC: 36 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000310 AC: 345 AN: 1112002

Other (OTH) AF: 0.000281 AC: 17 AN: 60396

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74492

African (AFR) AF: 0.0000481 AC: 2 AN: 41594

American (AMR) AF: 0.000718 AC: 11 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000306

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000296 AC: 36

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Progressive myoclonic epilepsy type 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.062	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	0.63	N
PhyloP100		3.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.39
Sift	Benign	0.32	T
Sift4G	Benign	0.30	T
Polyphen		0.35	B
Vest4		0.12
MVP		0.86
MPC		1.9
ClinPred		0.033	T
GERP RS		3.8
PromoterAI		-0.0086	Neutral
Varity_R		0.090
gMVP		0.72
Mutation Taster		=93/7	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: rs200873319; hg19: chr11-17793324;