rs12720445

chr12-5045880-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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. 13/19 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 1.77

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]

ACMG classification

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: {Benign=4, Likely_benign=3, 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 GnomAd at 900 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNA5	NM_002234.4	c.1733G>A	p.Arg578Lys	missense_variant	1/1	ENST00000252321.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNA5	ENST00000252321.5	c.1733G>A	p.Arg578Lys	missense_variant	1/1		NM_002234.4	P1

Frequencies

GnomAD3 genomes AF: 0.00591 AC: 900 AN: 152206 Hom.: 5 Cov.: 32

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.: 11 AF XY: 0.00520 AC XY: 706 AN XY: 135722

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.: 75 Cov.: 34 AF XY: 0.00875 AC XY: 6365 AN XY: 727206

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.: 5 Cov.: 32 AF XY: 0.00528 AC XY: 393 AN XY: 74486

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.: 13

Bravo AF: 0.00652

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.00930 AC: 80

ExAC AF: 0.00535 AC: 650

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00921

EpiControl AF: 0.00996

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	KCNA5: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Atrial fibrillation, familial, 7 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 29, 2023	- -

Brugada syndrome 1 Benign:1

Benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 16, 2017

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	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0078	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.23
Sift	Benign	0.034	D
Sift4G	Benign	0.47	T
Polyphen		0.0010	B
Vest4		0.19
MVP		1.0
MPC		0.64
ClinPred		0.0038	T
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

Other links and lift over

dbSNP: rs12720445; hg19: chr12-5155046;