12-4912062-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

episodic ataxia type 1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
episodic kinesigenic dyskinesia 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated autosomal dominant hypomagnesemia, Glaudemans type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
genetic developmental and epileptic encephalopathy
Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet

KCNA1 links:

ENSG00000256654 (HGNC:):

ENSG00000256654 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 21128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
KCNA1	NM_000217.3 link	c.684T>C	p.Cys228Cys	synonymous_variant	Exon 2 of 2	ENST00000382545.5	NP_000208.2	Q09470

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA1	ENST00000382545.5 link	c.684T>C	p.Cys228Cys	synonymous_variant	Exon 2 of 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

GnomAD2 exomes

AF:

0.492

AC:

123762

AN:

251376

AF XY:

0.490

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 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

African (AFR)

AF:

0.404

AC:

13514

AN:

33480

American (AMR)

AF:

0.526

AC:

23541

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.539

AC:

14080

AN:

26136

East Asian (EAS)

AF:

0.603

AC:

23945

AN:

39700

South Asian (SAS)

AF:

0.426

AC:

36762

AN:

86256

European-Finnish (FIN)

AF:

0.485

AC:

25884

AN:

53416

Middle Eastern (MID)

AF:

0.548

AC:

3161

AN:

5768

European-Non Finnish (NFE)

AF:

0.489

AC:

543932

AN:

1111926

Other (OTH)

AF:

0.495

AC:

29877

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

24445

48891

73336

97782

122227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15994

31988

47982

63976

79970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.471

AC:

71480

AN:

151876

Hom.:

17109

Cov.:

AF XY:

0.473

AC XY:

35059

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.402

AC:

16653

AN:

41412

American (AMR)

AF:

0.509

AC:

7787

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.529

AC:

1835

AN:

3466

East Asian (EAS)

AF:

0.600

AC:

3078

AN:

5132

South Asian (SAS)

AF:

0.429

AC:

2060

AN:

4802

European-Finnish (FIN)

AF:

0.484

AC:

5091

AN:

10518

Middle Eastern (MID)

AF:

0.634

AC:

185

AN:

292

European-Non Finnish (NFE)

AF:

0.491

AC:

33337

AN:

67948

Other (OTH)

AF:

0.490

AC:

1032

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1930

3860

5789

7719

9649

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.487

Hom.:

59723

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

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Episodic ataxia type 1

Benign:3

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:3

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Myokymia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

7.1

(source)

DANN

Benign

0.57

PhyloP100

1.7

PromoterAI

-0.0030

Neutral

(source)

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over