12-4912592-C-T

Variant names:

• chr12-4912592-C-T
• rs1555085798
• NM_000217.3:c.1214C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000217.3(KCNA1):​c.1214C>T​(p.Pro405Leu) 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P405A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: KCNA1 NM_000217.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.91
• Publications: 1 publications found

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]

KCNA1 Gene-Disease associations (from GenCC):

• episodic ataxia type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• episodic kinesigenic dyskinesia 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated autosomal dominant hypomagnesemia, Glaudemans type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet

ENSG00000256654 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000217.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-4912591-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 985808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 isolated autosomal dominant hypomagnesemia, Glaudemans type, episodic ataxia type 1, genetic developmental and epileptic encephalopathy, episodic kinesigenic dyskinesia 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 12-4912592-C-T is Pathogenic according to our data. Variant chr12-4912592-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 447609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000217.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA1	NM_000217.3	MANE Select	c.1214C>T	p.Pro405Leu	missense	Exon 2 of 2	NP_000208.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA1	ENST00000382545.5	TSL:4 MANE Select	c.1214C>T	p.Pro405Leu	missense	Exon 2 of 2	ENSP00000371985.3
	KCNA1	ENST00000639306.1	TSL:5	n.1052C>T		non_coding_transcript_exon	Exon 1 of 2	ENSP00000492506.1
	KCNA1	ENST00000639680.1	TSL:5	c.75+326C>T		intron	N/A	ENSP00000492218.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic ataxia type 1 Pathogenic:1

May 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNA1 protein function. ClinVar contains an entry for this variant (Variation ID: 447609). This missense change has been observed in individual(s) with neonatal onset epileptic encephalopathy (PMID: 27864847). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 405 of the KCNA1 protein (p.Pro405Leu).

not provided Pathogenic:1

Dec 22, 2016

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-8.9	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.72		Gain of catalytic residue at P405 (P = 0)
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		0.00080	Neutral
Varity_R		0.94
gMVP		1.0
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555085798; hg19: chr12-5021758;