rs4766310

Variant names:

• chr12-4912875-G-A
• rs4766310
• NM_000217.3:c.*9G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000217.3(KCNA1):​c.*9G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 1,596,498 control chromosomes in the GnomAD database, including 182,909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16131 hom., cov: 32)
  • Exomes 𝑓: 0.48 (166778 hom.)
• Consequence: KCNA1 NM_000217.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0550
• Publications: 16 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: Genomics England PanelApp, Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 12-4912875-G-A is Benign according to our data. Variant chr12-4912875-G-A is described in ClinVar as Benign. ClinVar VariationId is 195043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

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.*9G>A		3_prime_UTR	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.*9G>A		3_prime_UTR	Exon 2 of 2	ENSP00000371985.3	Q09470
	KCNA1	ENST00000639680.1	TSL:5	c.75+609G>A		intron	N/A	ENSP00000492218.1	A0A1W2PQM4
	KCNA1	ENST00000639306.1	TSL:5	n.*9G>A		non_coding_transcript_exon	Exon 1 of 2	ENSP00000492506.1	A0A1W2PRI2

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69220 AN: 151876 Hom.: 16127 Cov.: 32

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.476

GnomAD2 exomes AF: 0.480 AC: 120295 AN: 250746 AF XY: 0.478

Gnomad AFR exome AF: 0.376

Gnomad AMR exome AF: 0.524

Gnomad ASJ exome AF: 0.536

Gnomad EAS exome AF: 0.587

Gnomad FIN exome AF: 0.450

Gnomad NFE exome AF: 0.480

Gnomad OTH exome AF: 0.488

GnomAD4 exome AF: 0.478 AC: 690181 AN: 1444504 Hom.: 166778 Cov.: 28 AF XY: 0.476 AC XY: 342886 AN XY: 719802

African (AFR) AF: 0.382 AC: 12635 AN: 33062

American (AMR) AF: 0.521 AC: 23267 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 13973 AN: 26012

East Asian (EAS) AF: 0.580 AC: 22965 AN: 39600

South Asian (SAS) AF: 0.423 AC: 36291 AN: 85848

European-Finnish (FIN) AF: 0.453 AC: 24154 AN: 53370

Middle Eastern (MID) AF: 0.542 AC: 3111 AN: 5740

European-Non Finnish (NFE) AF: 0.479 AC: 524877 AN: 1096376

Other (OTH) AF: 0.483 AC: 28908 AN: 59814

GnomAD4 genome AF: 0.456 AC: 69241 AN: 151994 Hom.: 16131 Cov.: 32 AF XY: 0.456 AC XY: 33895 AN XY: 74306

African (AFR) AF: 0.379 AC: 15704 AN: 41402

American (AMR) AF: 0.500 AC: 7640 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 1836 AN: 3466

East Asian (EAS) AF: 0.580 AC: 3000 AN: 5170

South Asian (SAS) AF: 0.427 AC: 2055 AN: 4818

European-Finnish (FIN) AF: 0.449 AC: 4736 AN: 10548

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.480 AC: 32654 AN: 67988

Other (OTH) AF: 0.478 AC: 1010 AN: 2112

Alfa AF: 0.476 Hom.: 34108

Bravo AF: 0.461

Asia WGS AF: 0.494 AC: 1716 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Episodic ataxia type 1 (2)
-	-	1	Myokymia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.0
DANN	Benign	0.58
PhyloP100		0.055
Mutation Taster		=100/0	polymorphism (auto)

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: rs4766310; hg19: chr12-5022041; COSMIC: COSV66837429;