rs12720445

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002234.4(KCNA5):c.1733G>A(p.Arg578Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00878 in 1,614,122 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0059 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0091 ( 75 hom. )

Consequence

KCNA5
NM_002234.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 1.77

Variant links:

Genes affected

KCNA5 (HGNC:6224): (potassium voltage-gated channel subfamily A member 5) Potassium channels represent the most complex class of voltage-gated ino channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, the function of which could restore the resting membrane potential of beta cells after depolarization and thereby contribute to the regulation of insulin secretion. This gene is intronless, and the gene is clustered with genes KCNA1 and KCNA6 on chromosome 12. Defects in this gene are a cause of familial atrial fibrillation type 7 (ATFB7). [provided by RefSeq, May 2012]

KCNA5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007783413).

BP6

Variant 12-5045880-G-A is Benign according to our data. Variant chr12-5045880-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191573.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=4, Uncertain_significance=1}. Variant chr12-5045880-G-A is described in Lovd as [Benign]. Variant chr12-5045880-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 899 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA5	NM_002234.4 link	c.1733G>A	p.Arg578Lys	missense_variant	Exon 1 of 1	ENST00000252321.5	NP_002225.2	P22460-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA5	ENST00000252321.5 link	c.1733G>A	p.Arg578Lys	missense_variant	Exon 1 of 1	6	NM_002234.4	ENSP00000252321.3		P22460-1

Frequencies

GnomAD3 genomes

AF:

0.00591

AC:

900

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00972

Gnomad OTH

AF:

0.00764

GnomAD3 exomes

AF:

0.00540

AC:

1355

AN:

250972

Hom.:

AF XY:

0.00520

AC XY:

706

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.00253

Gnomad AMR exome

AF:

0.00408

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00973

Gnomad OTH exome

AF:

0.00636

GnomAD4 exome

AF:

0.00908

AC:

13274

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00875

AC XY:

6365

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00158

Gnomad4 AMR exome

AF:

0.00458

Gnomad4 ASJ exome

AF:

0.000689

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000545

Gnomad4 FIN exome

AF:

0.000844

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.00717

GnomAD4 genome

AF:

0.00590

AC:

899

AN:

152322

Hom.:

Cov.:

AF XY:

0.00528

AC XY:

393

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00216

Gnomad4 AMR

AF:

0.00470

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00970

Gnomad4 OTH

AF:

0.00756

Alfa

AF:

0.00898

Hom.:

Bravo

AF:

0.00652

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0125

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.00930

AC:

ExAC

AF:

0.00535

AC:

650

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00921

EpiControl

AF:

0.00996

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNA5: BS2 -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Atrial fibrillation, familial, 7

Uncertain:1Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 29, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome 1

Benign:1

Mar 16, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

The KCNA5 Arg578Lys has been previously identified in 2/95 "white" controls, in this study the variant did not affect potassium channel gating in transfected hamster oocytes, but did cause resistance to Quinidine (Simard C, et al., 2005). This KCNA5 Arg578Lys variant is found in the Exome Aggregation Consortium dataset at an elevated frequency (MAF=0.005; http://exac.broadinstitute.org/), suggesting that it is a common polymorphism (Ng, D et al., 2013). We identified this variant in one proband with Brugada syndrome, who has a normal QT and no family history of disease or SCD. Furthermore, computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to be well tolerated. In summary, based on the presence of KCNA5 Arg578Lys in controls, a high population frequency, and in silico tools predicting no deleterious affect on the protein, we classify this variant as "benign". -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.21

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0078

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.1

PrimateAI

Benign

0.42

PROVEAN

Benign

0.16

REVEL

Benign

0.23

Sift

Benign

0.034

Sift4G

Benign

0.47

Polyphen

0.0010

Vest4

0.19

MVP

1.0

MPC

0.64

ClinPred

0.0038

GERP RS

4.8

Varity_R

0.20

gMVP

0.16

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over