chr12-4912875-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000217.3(KCNA1):c.*9G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 1,596,498 control chromosomes in the GnomAD database, including 182,909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 16131 hom., cov: 32)

Exomes 𝑓: 0.48 ( 166778 hom. )

Consequence

KCNA1
NM_000217.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.0550

Publications

16 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 12-4912875-G-A is Benign according to our data. Variant chr12-4912875-G-A is described in ClinVar as [Benign]. Clinvar id is 195043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA1	NM_000217.3 link	c.*9G>A		3_prime_UTR_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.*9G>A		3_prime_UTR_variant	Exon 2 of 2	4	NM_000217.3	ENSP00000371985.3		Q09470

Frequencies

GnomAD3 genomes

AF:

0.456

AC:

69220

AN:

151876

Hom.:

16127

Cov.:

show subpopulations

Gnomad AFR

AF:

0.380

Gnomad AMI

AF:

0.462

Gnomad AMR

AF:

0.500

Gnomad ASJ

AF:

0.530

Gnomad EAS

AF:

0.580

Gnomad SAS

AF:

0.427

Gnomad FIN

AF:

0.449

Gnomad MID

AF:

0.623

Gnomad NFE

AF:

0.480

Gnomad OTH

AF:

0.476

GnomAD2 exomes

AF:

0.480

AC:

120295

AN:

250746

AF XY:

0.478

show subpopulations

Gnomad AFR exome

AF:

0.376

Gnomad AMR exome

AF:

0.524

Gnomad ASJ exome

AF:

0.536

Gnomad EAS exome

AF:

0.587

Gnomad FIN exome

AF:

0.450

Gnomad NFE exome

AF:

0.480

Gnomad OTH exome

AF:

0.488

GnomAD4 exome

AF:

0.478

AC:

690181

AN:

1444504

Hom.:

166778

Cov.:

AF XY:

0.476

AC XY:

342886

AN XY:

719802

show subpopulations

African (AFR)

AF:

0.382

AC:

12635

AN:

33062

American (AMR)

AF:

0.521

AC:

23267

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.537

AC:

13973

AN:

26012

East Asian (EAS)

AF:

0.580

AC:

22965

AN:

39600

South Asian (SAS)

AF:

0.423

AC:

36291

AN:

85848

European-Finnish (FIN)

AF:

0.453

AC:

24154

AN:

53370

Middle Eastern (MID)

AF:

0.542

AC:

3111

AN:

5740

European-Non Finnish (NFE)

AF:

0.479

AC:

524877

AN:

1096376

Other (OTH)

AF:

0.483

AC:

28908

AN:

59814

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

17205

34411

51616

68822

86027

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.456

AC:

69241

AN:

151994

Hom.:

16131

Cov.:

AF XY:

0.456

AC XY:

33895

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.379

AC:

15704

AN:

41402

American (AMR)

AF:

0.500

AC:

7640

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.530

AC:

1836

AN:

3466

East Asian (EAS)

AF:

0.580

AC:

3000

AN:

5170

South Asian (SAS)

AF:

0.427

AC:

2055

AN:

4818

European-Finnish (FIN)

AF:

0.449

AC:

4736

AN:

10548

Middle Eastern (MID)

AF:

0.629

AC:

185

AN:

294

European-Non Finnish (NFE)

AF:

0.480

AC:

32654

AN:

67988

Other (OTH)

AF:

0.478

AC:

1010

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1932

3863

5795

7726

9658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.476

Hom.:

34108

Bravo

AF:

0.461

Asia WGS

AF:

0.494

AC:

1716

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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 65% 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: 60. Only high quality variants are reported. -

May 09, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 26, 2019

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

- -

Episodic ataxia type 1

Benign:2

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

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

-0.95

CADD

Benign

3.0

(source)

DANN

Benign

0.58

PhyloP100

0.055

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

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chr12-4912875-G-A

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