NM_000217.3:c.-235C>A

Variant names:

• chr12-4911144-C-A
• rs113587682
• NM_000217.3:c.-235C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000217.3(KCNA1):​c.-235C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 596,152 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (9 hom.)
• Consequence: KCNA1 NM_000217.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.90
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 12-4911144-C-A is Benign according to our data. Variant chr12-4911144-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 309137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00112 (170/152294) while in subpopulation SAS AF = 0.0083 (40/4820). AF 95% confidence interval is 0.00626. There are 1 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

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.-235C>A		5_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.-235C>A		5_prime_UTR	Exon 2 of 2	ENSP00000371985.3	Q09470
	ENSG00000256654	ENST00000541095.1	TSL:3	n.105+672C>A		intron	N/A
	KCNA1	ENST00000543874.3	TSL:2	n.105+672C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152176 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00187 AC: 830 AN: 443858 Hom.: 9 Cov.: 0 AF XY: 0.00237 AC XY: 554 AN XY: 234000

African (AFR) AF: 0.000326 AC: 4 AN: 12272

American (AMR) AF: 0.00207 AC: 38 AN: 18386

Ashkenazi Jewish (ASJ) AF: 0.000443 AC: 6 AN: 13540

East Asian (EAS) AF: 0.00 AC: 0 AN: 30752

South Asian (SAS) AF: 0.00970 AC: 440 AN: 45344

European-Finnish (FIN) AF: 0.000137 AC: 4 AN: 29096

Middle Eastern (MID) AF: 0.00877 AC: 17 AN: 1938

European-Non Finnish (NFE) AF: 0.00102 AC: 273 AN: 266764

Other (OTH) AF: 0.00186 AC: 48 AN: 25766

GnomAD4 genome AF: 0.00112 AC: 170 AN: 152294 Hom.: 1 Cov.: 31 AF XY: 0.00133 AC XY: 99 AN XY: 74472

African (AFR) AF: 0.000217 AC: 9 AN: 41562

American (AMR) AF: 0.00307 AC: 47 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00830 AC: 40 AN: 4820

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000956 AC: 65 AN: 68020

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000847 Hom.: 0

Bravo AF: 0.00104

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Episodic ataxia type 1 (1)
-	-	1	Myokymia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.4
DANN	Benign	0.84
PhyloP100		-1.9
Mutation Taster		=300/0	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: rs113587682; hg19: chr12-5020310;