rs150993414

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_001112741.2(KCNC1):​c.709C>T​(p.Arg237Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,614,112 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

KCNC1
NM_001112741.2 missense

Scores

10
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.45
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 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=0.35825133).
BP6
Variant 11-17771803-C-T is Benign according to our data. Variant chr11-17771803-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 578002.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
High AC in GnomAdExome4 at 59 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNC1NM_001112741.2 linkuse as main transcriptc.709C>T p.Arg237Trp missense_variant 2/4 ENST00000265969.8 NP_001106212.1
KCNC1NM_004976.4 linkuse as main transcriptc.709C>T p.Arg237Trp missense_variant 2/2 NP_004967.1
KCNC1XM_047426916.1 linkuse as main transcriptc.709C>T p.Arg237Trp missense_variant 2/4 XP_047282872.1
KCNC1XR_930866.3 linkuse as main transcriptn.1931C>T non_coding_transcript_exon_variant 2/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNC1ENST00000265969.8 linkuse as main transcriptc.709C>T p.Arg237Trp missense_variant 2/45 NM_001112741.2 ENSP00000265969 P1P48547-2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152230
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000596
AC:
15
AN:
251486
Hom.:
0
AF XY:
0.0000441
AC XY:
6
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000217
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000791
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000404
AC:
59
AN:
1461882
Hom.:
0
Cov.:
31
AF XY:
0.0000358
AC XY:
26
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000504
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152230
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.0000453
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000741
AC:
9
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Progressive myoclonic epilepsy type 7 Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 21, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityAug 12, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
0.0063
T
BayesDel_noAF
Uncertain
0.040
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.52
D;.
Eigen
Benign
0.039
Eigen_PC
Benign
0.046
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.36
T;T
MetaSVM
Uncertain
0.28
D
MutationAssessor
Benign
1.3
L;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-1.2
N;N
REVEL
Uncertain
0.64
Sift
Benign
0.049
D;T
Sift4G
Uncertain
0.024
D;D
Polyphen
0.83
P;.
Vest4
0.42
MVP
0.84
MPC
2.3
ClinPred
0.13
T
GERP RS
3.9
Varity_R
0.074
gMVP
0.81

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.

Other links and lift over

dbSNP: rs150993414; hg19: chr11-17793350; API