rs4766309

Positions:

• chr12-4912818-T-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000217.3(KCNA1):​c.1440T>A​(p.Thr480=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 1,613,506 control chromosomes in the GnomAD database, including 400,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43764 hom., cov: 31)
  • Exomes 𝑓: 0.70 (357053 hom.)
• Consequence: KCNA1 NM_000217.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.46

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 12-4912818-T-A is Benign according to our data. Variant chr12-4912818-T-A is described in ClinVar as [Benign]. Clinvar id is 129313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-4912818-T-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.939 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNA1	NM_000217.3	c.1440T>A	p.Thr480=	synonymous_variant	2/2	ENST00000382545.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNA1	ENST00000382545.5	c.1440T>A	p.Thr480=	synonymous_variant	2/2	4	NM_000217.3	P1
	ENST00000640877.1	n.606+2346T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.753 AC: 114409 AN: 152002 Hom.: 43710 Cov.: 31

Gnomad AFR AF: 0.855

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.961

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.744

GnomAD3 exomes AF: 0.738 AC: 185521 AN: 251334 Hom.: 69311 AF XY: 0.733 AC XY: 99589 AN XY: 135856

Gnomad AFR exome AF: 0.858

Gnomad AMR exome AF: 0.756

Gnomad ASJ exome AF: 0.690

Gnomad EAS exome AF: 0.965

Gnomad SAS exome AF: 0.728

Gnomad FIN exome AF: 0.761

Gnomad NFE exome AF: 0.682

Gnomad OTH exome AF: 0.719

GnomAD4 exome AF: 0.696 AC: 1017485 AN: 1461386 Hom.: 357053 Cov.: 45 AF XY: 0.696 AC XY: 506360 AN XY: 727024

Gnomad4 AFR exome AF: 0.861

Gnomad4 AMR exome AF: 0.754

Gnomad4 ASJ exome AF: 0.690

Gnomad4 EAS exome AF: 0.951

Gnomad4 SAS exome AF: 0.730

Gnomad4 FIN exome AF: 0.758

Gnomad4 NFE exome AF: 0.673

Gnomad4 OTH exome AF: 0.720

GnomAD4 genome AF: 0.753 AC: 114520 AN: 152120 Hom.: 43764 Cov.: 31 AF XY: 0.759 AC XY: 56479 AN XY: 74390

Gnomad4 AFR AF: 0.855

Gnomad4 AMR AF: 0.750

Gnomad4 ASJ AF: 0.681

Gnomad4 EAS AF: 0.961

Gnomad4 SAS AF: 0.747

Gnomad4 FIN AF: 0.770

Gnomad4 NFE AF: 0.678

Gnomad4 OTH AF: 0.747

Alfa AF: 0.697 Hom.: 12114

Bravo AF: 0.760

Asia WGS AF: 0.867 AC: 3014 AN: 3478

EpiCase AF: 0.680

EpiControl AF: 0.687

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic ataxia type 1 Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 89% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 83. Only high quality variants are reported. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2019	- -

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	-0.63
CADD	Benign	9.4
DANN	Benign	0.69

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: rs4766309; hg19: chr12-5021984;