chr12-4912102-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_000217.3(KCNA1):​c.724G>C​(p.Ala242Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 31)

Consequence

KCNA1
NM_000217.3 missense

Scores

12
6
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.81
Variant links:
Genes affected
KCNA1 (HGNC:6218): (potassium voltage-gated channel subfamily A member 1) This gene encodes a voltage-gated delayed potassium channel that is phylogenetically related to the Drosophila Shaker channel. The encoded protein has six putative transmembrane segments (S1-S6), and the loop between S5 and S6 forms the pore and contains the conserved selectivity filter motif (GYGD). The functional channel is a homotetramer. The N-terminus of the channel is associated with beta subunits that can modify the inactivation properties of the channel as well as affect expression levels. The C-terminus of the channel is complexed to a PDZ domain protein that is responsible for channel targeting. Mutations in this gene have been associated with myokymia with periodic ataxia (AEMK). [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the KCNA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 33 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 3.3255 (above the threshold of 3.09). Trascript score misZ: 3.8671 (above the threshold of 3.09). GenCC associations: The gene is linked to episodic kinesigenic dyskinesia 1, episodic ataxia type 1, developmental and epileptic encephalopathy, isolated autosomal dominant hypomagnesemia, Glaudemans type.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.975
PP5
Variant 12-4912102-G-C is Pathogenic according to our data. Variant chr12-4912102-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13489.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNA1NM_000217.3 linkc.724G>C p.Ala242Pro missense_variant Exon 2 of 2 ENST00000382545.5 NP_000208.2 Q09470

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNA1ENST00000382545.5 linkc.724G>C p.Ala242Pro missense_variant Exon 2 of 2 4 NM_000217.3 ENSP00000371985.3 Q09470

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
60
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Myokymia 1 Pathogenic:1
Oct 01, 2000
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not provided Pathogenic:1
Oct 14, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.98
D
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.81
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.1
M
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-4.4
D
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.013
D
Polyphen
0.98
D
Vest4
0.94
MutPred
0.80
Gain of catalytic residue at A242 (P = 0);
MVP
0.99
MPC
2.6
ClinPred
0.97
D
GERP RS
4.1
Varity_R
0.96
gMVP
0.98

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: rs28933381; hg19: chr12-5021268; API