11-17771777-G-T

Position:

chr11-17771777-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

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 (★★).

Frequency

Genomes: 𝑓 0.00032 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

KCNC1
NM_001112741.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.95

Variant links:

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 links:

KCNC1 (HGNC:):

KCNC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNC1. . Gene score misZ 4.5189 (greater than the threshold 3.09). Trascript score misZ 5.1707 (greater than threshold 3.09). GenCC has associacion of gene with progressive myoclonic epilepsy type 7, progressive myoclonus epilepsy, complex neurodevelopmental disorder.

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 [Likely_benign]. Clinvar id is 475358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17771777-G-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 49 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNC1	NM_001112741.2 linkuse as main transcript	c.683G>T	p.Arg228Leu	missense_variant	2/4	ENST00000265969.8	NP_001106212.1	P48547-2
KCNC1	NM_004976.4 linkuse as main transcript	c.683G>T	p.Arg228Leu	missense_variant	2/2		NP_004967.1	P48547-1
KCNC1	XM_047426916.1 linkuse as main transcript	c.683G>T	p.Arg228Leu	missense_variant	2/4		XP_047282872.1
KCNC1	XR_930866.3 linkuse as main transcript	n.1905G>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNC1	ENST00000265969.8 linkuse as main transcript	c.683G>T	p.Arg228Leu	missense_variant	2/4	5	NM_001112741.2	ENSP00000265969.7		P48547-2

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000314

AC:

AN:

251490

Hom.:

AF XY:

0.000309

AC XY:

AN XY:

135918

show subpopulations

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 SAS exome

AF:

0.000425

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.:

Cov.:

AF XY:

0.000290

AC XY:

211

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000417

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000310

Gnomad4 OTH exome

AF:

0.000281

GnomAD4 genome

AF:

0.000322

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000718

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000421

Hom.:

Bravo

AF:

0.000306

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000296

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Progressive myoclonic epilepsy type 7

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.057

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.056

MetaRNN

Benign

0.062

T;T

MetaSVM

Uncertain

-0.10

MutationAssessor

Benign

0.63

N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.0

N;N

REVEL

Uncertain

0.39

Sift

Benign

0.32

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.35

B;.

Vest4

0.12

MVP

0.86

MPC

1.9

ClinPred

0.033

GERP RS

3.8

Varity_R

0.090

gMVP

0.72

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over