chr12-4911929-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP2PP3_ModeratePP5

The NM_000217.3(KCNA1):​c.551T>G​(p.Phe184Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F184V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

KCNA1
NM_000217.3 missense

Scores

16
2
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.96
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-4911928-T-G is described in Lovd as [Likely_pathogenic].
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, 0.893
PP5
Variant 12-4911929-T-G is Pathogenic according to our data. Variant chr12-4911929-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 13484.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNA1NM_000217.3 linkc.551T>G p.Phe184Cys missense_variant 2/2 ENST00000382545.5 NP_000208.2 Q09470

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNA1ENST00000382545.5 linkc.551T>G p.Phe184Cys missense_variant 2/24 NM_000217.3 ENSP00000371985.3 Q09470

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Episodic ataxia type 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 1995- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
31
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.98
D
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.30
D
MetaRNN
Pathogenic
0.89
D
MetaSVM
Uncertain
0.60
D
MutationAssessor
Pathogenic
4.3
H
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-7.6
D
REVEL
Pathogenic
0.75
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.91
MutPred
0.58
Gain of catalytic residue at L186 (P = 0);
MVP
0.96
MPC
2.8
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.98
gMVP
0.95

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: rs104894357; hg19: chr12-5021095; API