chr12-4912102-G-T

Variant names:

• chr12-4912102-G-T
• rs28933381
• NM_000217.3:c.724G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_000217.3(KCNA1):​c.724G>T​(p.Ala242Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A242V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCNA1 NM_000217.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.81
• Publications: 18 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Genomics England PanelApp, Orphanet
• episodic kinesigenic dyskinesia 1

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

  Inheritance: AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P
• isolated autosomal dominant hypomagnesemia, Glaudemans type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000256654 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr12-4912102-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13489.Status of the report is criteria_provided_single_submitter, 1 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 episodic ataxia type 1, genetic developmental and epileptic encephalopathy, isolated autosomal dominant hypomagnesemia, Glaudemans type, episodic kinesigenic dyskinesia 1.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA1	NM_000217.3	MANE Select	c.724G>T	p.Ala242Ser	missense	Exon 2 of 2	NP_000208.2	Q09470

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA1	ENST00000382545.5	TSL:4 MANE Select	c.724G>T	p.Ala242Ser	missense	Exon 2 of 2	ENSP00000371985.3	Q09470
	KCNA1	ENST00000639306.1	TSL:5	n.562G>T		non_coding_transcript_exon	Exon 1 of 2	ENSP00000492506.1	A0A1W2PRI2
	ENSG00000256654	ENST00000541095.1	TSL:3	n.105+1630G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 60

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Episodic ataxia type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.50	N
PhyloP100		6.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.46
Sift	Benign	0.28	T
Sift4G	Benign	0.50	T
Polyphen		0.0040	B
Vest4		0.36
MutPred		0.69		Gain of catalytic residue at K246 (P = 0.0071)
MVP		0.91
MPC		1.2
ClinPred		0.81	D
GERP RS		4.1
PromoterAI		-0.00040	Neutral
Varity_R		0.32
gMVP		0.74
Mutation Taster		=58/42	polymorphism

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: rs28933381; hg19: chr12-5021268;