rs104894354

Variant names:

• chr12-4912054-A-G
• rs104894354
• NM_000217.3:c.676A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_000217.3(KCNA1):​c.676A>G​(p.Thr226Ala) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCNA1 NM_000217.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.26

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]

ENSG00000256654 (HGNC:):

ACMG classification

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, 0.956
• PP5: Variant 12-4912054-A-G is Pathogenic according to our data. Variant chr12-4912054-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13486.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA1	NM_000217.3	c.676A>G	p.Thr226Ala	missense_variant	Exon 2 of 2	ENST00000382545.5	NP_000208.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA1	ENST00000382545.5	c.676A>G	p.Thr226Ala	missense_variant	Exon 2 of 2	4	NM_000217.3	ENSP00000371985.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Episodic ataxia type 1 Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNA1: PP1:Strong, PM1, PM2, PM5, PP2, PP3, PS3:Supporting, PS4:Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.048	D
Polyphen		0.27	B
Vest4		0.89
MutPred		0.80		Gain of catalytic residue at F221 (P = 0);
MVP		0.96
MPC		2.3
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.73
gMVP		0.84

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

Other links and lift over

dbSNP: rs104894354; hg19: chr12-5021220;