NM_000217.3:c.684T>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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Genomics England PanelApp, Orphanet
episodic kinesigenic dyskinesia 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
genetic developmental and epileptic encephalopathy
Inheritance: AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P
isolated autosomal dominant hypomagnesemia, Glaudemans type
Inheritance: AD Classification: SUPPORTIVE Submitted by: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000217.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA1	NM_000217.3	MANE Select	c.684T>C	p.Cys228Cys	synonymous	Exon 2 of 2	NP_000208.2	Q09470

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNA1	ENST00000382545.5	TSL:4 MANE Select	c.684T>C	p.Cys228Cys	synonymous	Exon 2 of 2	ENSP00000371985.3	Q09470
KCNA1	ENST00000639306.1	TSL:5	n.522T>C		non_coding_transcript_exon	Exon 1 of 2	ENSP00000492506.1	A0A1W2PRI2
ENSG00000256654	ENST00000541095.1	TSL:3	n.105+1590T>C		intron	N/A

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Episodic ataxia type 1 (3)

not provided (3)

Myokymia (1)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over