chr12-4912062-T-C

Position:

chr12-4912062-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000217.3(KCNA1):c.684T>C(p.Cys228Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,613,674 control chromosomes in the GnomAD database, including 193,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 17109 hom., cov: 31)

Exomes 𝑓: 0.49 ( 176344 hom. )

Consequence

KCNA1
NM_000217.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.74

Variant links:

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 links:

ENSG00000256654 (HGNC:):

ENSG00000256654 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 12-4912062-T-C is Benign according to our data. Variant chr12-4912062-T-C is described in ClinVar as [Benign]. Clinvar id is 21128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-4912062-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.74 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA1	NM_000217.3 linkuse as main transcript	c.684T>C	p.Cys228Cys	synonymous_variant	2/2	ENST00000382545.5	NP_000208.2	Q09470

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNA1	ENST00000382545.5 linkuse as main transcript	c.684T>C	p.Cys228Cys	synonymous_variant	2/2	4	NM_000217.3	ENSP00000371985.3		Q09470

Frequencies

GnomAD3 genomes

AF:

0.471

AC:

71454

AN:

151758

Hom.:

17102

Cov.:

show subpopulations

Gnomad AFR

AF:

0.402

Gnomad AMI

AF:

0.463

Gnomad AMR

AF:

0.510

Gnomad ASJ

AF:

0.529

Gnomad EAS

AF:

0.600

Gnomad SAS

AF:

0.430

Gnomad FIN

AF:

0.484

Gnomad MID

AF:

0.627

Gnomad NFE

AF:

0.491

Gnomad OTH

AF:

0.487

GnomAD3 exomes

AF:

0.492

AC:

123762

AN:

251376

Hom.:

30809

AF XY:

0.490

AC XY:

66576

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.398

Gnomad AMR exome

AF:

0.530

Gnomad ASJ exome

AF:

0.536

Gnomad EAS exome

AF:

0.606

Gnomad SAS exome

AF:

0.423

Gnomad FIN exome

AF:

0.485

Gnomad NFE exome

AF:

0.492

Gnomad OTH exome

AF:

0.498

GnomAD4 exome

AF:

0.489

AC:

714696

AN:

1461798

Hom.:

176344

Cov.:

AF XY:

0.487

AC XY:

354324

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.404

Gnomad4 AMR exome

AF:

0.526

Gnomad4 ASJ exome

AF:

0.539

Gnomad4 EAS exome

AF:

0.603

Gnomad4 SAS exome

AF:

0.426

Gnomad4 FIN exome

AF:

0.485

Gnomad4 NFE exome

AF:

0.489

Gnomad4 OTH exome

AF:

0.495

GnomAD4 genome

AF:

0.471

AC:

71480

AN:

151876

Hom.:

17109

Cov.:

AF XY:

0.473

AC XY:

35059

AN XY:

74180

show subpopulations

Gnomad4 AFR

AF:

0.402

Gnomad4 AMR

AF:

0.509

Gnomad4 ASJ

AF:

0.529

Gnomad4 EAS

AF:

0.600

Gnomad4 SAS

AF:

0.429

Gnomad4 FIN

AF:

0.484

Gnomad4 NFE

AF:

0.491

Gnomad4 OTH

AF:

0.490

Alfa

AF:

0.493

Hom.:

38660

Bravo

AF:

0.475

Asia WGS

AF:

0.517

AC:

1795

AN:

3478

EpiCase

AF:

0.502

EpiControl

AF:

0.506

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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 71% 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: 66. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Episodic ataxia type 1

Benign:3

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

-0.58

CADD

Benign

7.1

DANN

Benign

0.57

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over