12-4913272-C-T

Position:

• chr12-4913272-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000217.3(KCNA1):​c.*406C>T variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.47 in 268,744 control chromosomes in the GnomAD database, including 30,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18121 hom., cov: 33)
  • Exomes 𝑓: 0.45 (12171 hom.)
• Consequence: KCNA1 NM_000217.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.57

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=-0.62).
• BP6: Variant 12-4913272-C-T is Benign according to our data. Variant chr12-4913272-C-T is described in ClinVar as [Benign]. Clinvar id is 309154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA1	NM_000217.3	c.*406C>T		3_prime_UTR_variant	2/2	ENST00000382545.5	NP_000208.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNA1	ENST00000382545.5	c.*406C>T		3_prime_UTR_variant	2/2	4	NM_000217.3	ENSP00000371985	P1
	ENST00000640877.1	n.606+2800C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73798 AN: 151888 Hom.: 18120 Cov.: 33

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.490

GnomAD4 exome AF: 0.450 AC: 52488 AN: 116738 Hom.: 12171 Cov.: 0 AF XY: 0.443 AC XY: 27265 AN XY: 61494

Gnomad4 AFR exome AF: 0.424

Gnomad4 AMR exome AF: 0.520

Gnomad4 ASJ exome AF: 0.487

Gnomad4 EAS exome AF: 0.555

Gnomad4 SAS exome AF: 0.382

Gnomad4 FIN exome AF: 0.465

Gnomad4 NFE exome AF: 0.450

Gnomad4 OTH exome AF: 0.466

GnomAD4 genome AF: 0.486 AC: 73821 AN: 152006 Hom.: 18121 Cov.: 33 AF XY: 0.485 AC XY: 36040 AN XY: 74290

Gnomad4 AFR AF: 0.473

Gnomad4 AMR AF: 0.512

Gnomad4 ASJ AF: 0.530

Gnomad4 EAS AF: 0.576

Gnomad4 SAS AF: 0.427

Gnomad4 FIN AF: 0.468

Gnomad4 NFE AF: 0.484

Gnomad4 OTH AF: 0.493

Alfa AF: 0.489 Hom.: 26177

Bravo AF: 0.493

Asia WGS AF: 0.495 AC: 1717 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Episodic ataxia type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.3
DANN	Benign	0.60

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: rs4766311; hg19: chr12-5022438; COSMIC: COSV66837385;