12-4912674-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000217.3(KCNA1):c.1296C>G(p.Ser432Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00377 in 1,612,308 control chromosomes in the GnomAD database, including 326 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 33 hom., cov: 30)

Exomes 𝑓: 0.0037 ( 293 hom. )

Consequence

KCNA1
NM_000217.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.79

Publications

4 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 12-4912674-C-G is Benign according to our data. Variant chr12-4912674-C-G is described in ClinVar as Benign. ClinVar VariationId is 195045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.79 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.109 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.1296C>G	p.Ser432Ser	synonymous	Exon 2 of 2	NP_000208.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNA1	ENST00000382545.5	TSL:4 MANE Select	c.1296C>G	p.Ser432Ser	synonymous	Exon 2 of 2	ENSP00000371985.3
KCNA1	ENST00000639680.1	TSL:5	c.75+408C>G		intron	N/A	ENSP00000492218.1
KCNA1	ENST00000639306.1	TSL:5	n.1134C>G		non_coding_transcript_exon	Exon 1 of 2	ENSP00000492506.1

Frequencies

GnomAD3 genomes

AF:

0.00441

AC:

665

AN:

150776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000537

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000733

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.117

Gnomad SAS

AF:

0.00527

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00385

GnomAD2 exomes

AF:

0.00928

AC:

2329

AN:

250886

AF XY:

0.00842

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.119

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00371

AC:

5415

AN:

1461406

Hom.:

293

Cov.:

AF XY:

0.00365

AC XY:

2657

AN XY:

727022

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33480

American (AMR)

AF:

0.000268

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.119

AC:

4720

AN:

39700

South Asian (SAS)

AF:

0.00291

AC:

251

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52940

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000683

AC:

AN:

1112010

Other (OTH)

AF:

0.00566

AC:

342

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

375

750

1125

1500

1875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<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:

0.00439

AC:

662

AN:

150902

Hom.:

Cov.:

AF XY:

0.00499

AC XY:

367

AN XY:

73584

show subpopulations

African (AFR)

AF:

0.000535

AC:

AN:

41086

American (AMR)

AF:

0.000732

AC:

AN:

15024

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.116

AC:

589

AN:

5062

South Asian (SAS)

AF:

0.00528

AC:

AN:

4738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67844

Other (OTH)

AF:

0.00381

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.000491

Hom.:

Bravo

AF:

0.00543

Asia WGS

AF:

0.0360

AC:

127

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Episodic ataxia type 1 (2)

not provided (2)

not specified (2)

Myokymia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

5.8

(source)

DANN

Benign

0.66

PhyloP100

1.8

PromoterAI

-0.0058

Neutral

(source)

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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