rs755408841

chr12-5044691-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PP3_Strong BP6 BS2

The NM_002234.4(KCNA5):c.544G>A(p.Gly182Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000805 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: KCNA5 NM_002234.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 9.93

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 Likely_benign. Variant got -1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• BP6: Variant 12-5044691-G-A is Benign according to our data. Variant chr12-5044691-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 469594.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNA5	NM_002234.4	c.544G>A	p.Gly182Arg	missense_variant	1/1	ENST00000252321.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNA5	ENST00000252321.5	c.544G>A	p.Gly182Arg	missense_variant	1/1		NM_002234.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000207 AC: 52 AN: 250716 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135674

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000814 AC: 119 AN: 1461746 Hom.: 0 Cov.: 31 AF XY: 0.0000729 AC XY: 53 AN XY: 727180

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74448

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2020	Reported in association with idiopathic pulmonary hypertension; patient-specific clinical data and segregation data were not provided (Remillard et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In vitro functional studies suggest that G182R may affect the KCNA5 channel function (Burg et al., 2010); however, it is not clear how well these studies reproduce in vivo condition; This variant is associated with the following publications: (PMID: 20018952, 17267549, 28341588) -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 24, 2018	p.Gly182Arg (G182R; c.544G>A) in exon 1 of the KCNA5 gene (NM_002234.3; ENST00000252321.4) Chromosome position: 12:5153857 G / A Found in a male patient with early-onset lone atrial fibrillation. The KCNA5 gene has been associated with familial atrial fibrillation. Based on the information reviewed below, including its relatively high frequency among individuals with Latino ancestry like our patient, we classify it as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has previously been reported in two individuals with idiopathic pulmonary hypertension both taking part in the same study (Remillard et al. 2007; PMID: 17267549), and one with Brugada syndrome (Proost et al. 2017). There is no informative segregation information. Of note, 12% of the participants in the Remillard study were Hispanic. The researchers reported that this missense change affects KCNA5 channel inactivation and localization in vitro (Burg et al. 2010; PMID: 20018952), although it does form functional channels. According to these authors, the variant is located in the highly conserved NH2-terminal tetramerization domain (T1) of KV channels which is important for proper channel assembly, association with regulatory subunits, and localization of the channel to the plasma membrane. They note that the glycine at position 182 is 100% identical in the T1 domains of all 17 human KCNA (KV1), KV2 (KCNB), KV3 (KCNC), and KV4 (KCND) subunits examined (KCNA1–7, KCNA10, KCNB1–2, KCNC1–4, and KCND1–3). This is a distinctly nonconservative amino acid change, resulting in the replacement of a nonpolar Glycine with a positively-charge Arginine with a much larger side-chain. Glycine at this location is absolutely conserved across ~100 vertebrate species for which we have data. The adjacent residues are also very highly conserved. There are no Likely Pathogenic or Pathogenic variants currently listed in ClinVar within 10 amino acids to either side. This variant was reported in 54 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 41 Latinos (for the highest allele frequency: 0.12%), 3 East Asians, 8 non-Finnish Europeans, 1 African, and 1 “Other” ancestry individual. It is present at a higher frequency than would be expected for a pathogenic variant, and is particularly prevalent among individuals with our patient’s Latino ancestry—which suggests that it might be a benign ethnicity-specific variant. The phenotype of the individuals in gnomAD is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 05, 2020	The KCNA5 c.544G>A; p.Gly182Arg variant (rs755408841) is reported in the literature in an individual affected with pulmonary arterial hypertension (Burg 2010). This variant is found in the Latino population with an overall allele frequency of 0.11% (40/35432 alleles in the Genome Aggregation Database. The glycine at codon 182 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.924). Functional studies suggest that the variant protein forms functional channels when expressed in cultured cells, but it exhibits reduced processing and altered inactivation kinetics (Burg 2010). Although the population frequency of this variant appears inconsistent with disease, due to conflicting information, the clinical significance of the p.Gly182Arg variant is uncertain at this time. References: Burg ED et al. Tetramerization domain mutations in KCNA5 affect channel kinetics and cause abnormal trafficking patterns. Am J Physiol Cell Physiol. 2010 Mar;298(3):C496-509. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.95		Gain of solvent accessibility (P = 0.0171);
MVP		0.98
MPC		1.6
ClinPred		0.61	D
GERP RS		4.7
Varity_R		0.86
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs755408841; hg19: chr12-5153857; COSMIC: COSV52906752;