chr12-5044691-G-A
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PP3_StrongBP6BS2
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
NM_002234.4 missense
Scores
15
3
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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: {Likely_benign=1, Uncertain_significance=2}.
BS2
High AC in GnomAd4 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: 11AN: 152154Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000207 AC: 52AN: 250716Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135674
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GnomAD4 exome AF: 0.0000814 AC: 119AN: 1461746Hom.: 0 Cov.: 31 AF XY: 0.0000729 AC XY: 53AN XY: 727180
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GnomAD4 genome AF: 0.0000722 AC: 11AN: 152272Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74448
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
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. - |
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) - |
Atrial fibrillation, familial, 7 Uncertain:1Benign: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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of solvent accessibility (P = 0.0171);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at