12-4912182-G-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.804G>C(p.Thr268Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 1,612,204 control chromosomes in the GnomAD database, including 215,863 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T268T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.51 ( 19642 hom., cov: 27)

Exomes 𝑓: 0.52 ( 196221 hom. )

Consequence

KCNA1
NM_000217.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.640

Publications

23 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=-0.59).

BP6

Variant 12-4912182-G-C is Benign according to our data. Variant chr12-4912182-G-C is described in ClinVar as Benign. ClinVar VariationId is 21130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.64 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.626 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.804G>C	p.Thr268Thr	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.804G>C	p.Thr268Thr	synonymous	Exon 2 of 2	ENSP00000371985.3	Q09470
KCNA1	ENST00000639306.1	TSL:5	n.642G>C		non_coding_transcript_exon	Exon 1 of 2	ENSP00000492506.1	A0A1W2PRI2
ENSG00000256654	ENST00000541095.1	TSL:3	n.105+1710G>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.508

AC:

76460

AN:

150484

Hom.:

19629

Cov.:

show subpopulations

Gnomad AFR

AF:

0.460

Gnomad AMI

AF:

0.521

Gnomad AMR

AF:

0.581

Gnomad ASJ

AF:

0.580

Gnomad EAS

AF:

0.645

Gnomad SAS

AF:

0.481

Gnomad FIN

AF:

0.487

Gnomad MID

AF:

0.656

Gnomad NFE

AF:

0.511

Gnomad OTH

AF:

0.528

GnomAD2 exomes

AF:

0.532

AC:

133633

AN:

251292

AF XY:

0.528

show subpopulations

Gnomad AFR exome

AF:

0.455

Gnomad AMR exome

AF:

0.632

Gnomad ASJ exome

AF:

0.590

Gnomad EAS exome

AF:

0.656

Gnomad FIN exome

AF:

0.487

Gnomad NFE exome

AF:

0.511

Gnomad OTH exome

AF:

0.530

GnomAD4 exome

AF:

0.516

AC:

753596

AN:

1461602

Hom.:

196221

Cov.:

AF XY:

0.514

AC XY:

373941

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.461

AC:

15444

AN:

33478

American (AMR)

AF:

0.625

AC:

27958

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.590

AC:

15413

AN:

26136

East Asian (EAS)

AF:

0.642

AC:

25472

AN:

39700

South Asian (SAS)

AF:

0.476

AC:

41067

AN:

86258

European-Finnish (FIN)

AF:

0.487

AC:

25971

AN:

53298

Middle Eastern (MID)

AF:

0.592

AC:

3417

AN:

5768

European-Non Finnish (NFE)

AF:

0.510

AC:

567260

AN:

1111850

Other (OTH)

AF:

0.523

AC:

31594

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

23751

47501

71252

95002

118753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16524

33048

49572

66096

82620

<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:

0.508

AC:

76505

AN:

150602

Hom.:

19642

Cov.:

AF XY:

0.510

AC XY:

37388

AN XY:

73348

show subpopulations

African (AFR)

AF:

0.460

AC:

18844

AN:

40986

American (AMR)

AF:

0.581

AC:

8818

AN:

15170

Ashkenazi Jewish (ASJ)

AF:

0.580

AC:

2005

AN:

3458

East Asian (EAS)

AF:

0.645

AC:

3240

AN:

5024

South Asian (SAS)

AF:

0.480

AC:

2249

AN:

4686

European-Finnish (FIN)

AF:

0.487

AC:

5004

AN:

10272

Middle Eastern (MID)

AF:

0.661

AC:

193

AN:

292

European-Non Finnish (NFE)

AF:

0.510

AC:

34570

AN:

67720

Other (OTH)

AF:

0.532

AC:

1110

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1817

3634

5450

7267

9084

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

674

1348

2022

2696

3370

<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:

0.480

Hom.:

5126

Bravo

AF:

0.519

Asia WGS

AF:

0.576

AC:

1998

AN:

3478

EpiCase

AF:

0.524

EpiControl

AF:

0.526

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)

Hereditary episodic ataxia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

5.4

(source)

DANN

Benign

0.73

PhyloP100

-0.64

PromoterAI

0.033

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