12-4911144-C-A

Variant summary

Our verdict is Benign. Variant got -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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 169 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNA1	NM_000217.3	c.-235C>A		5_prime_UTR_variant	2/2	ENST00000382545.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNA1	ENST00000382545.5	c.-235C>A		5_prime_UTR_variant	2/2	4	NM_000217.3	P1
	ENST00000640877.1	n.606+672C>A		intron_variant, non_coding_transcript_variant		5

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

Gnomad4 AFR exome AF: 0.000326

Gnomad4 AMR exome AF: 0.00207

Gnomad4 ASJ exome AF: 0.000443

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00970

Gnomad4 FIN exome AF: 0.000137

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.00186

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

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00830

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000956

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000847 Hom.: 0

Bravo AF: 0.00104

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic ataxia type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Myokymia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

KCNA1: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	3.4
Dann	Benign	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: rs113587682; hg19: chr12-5020310;