rs755408841

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 9.93

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

atrial fibrillation, familial, 7
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KCNA5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 VariationId is 469594.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA5	NM_002234.4 link	c.544G>A	p.Gly182Arg	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.544G>A	p.Gly182Arg	missense_variant	Exon 1 of 1	6	NM_002234.4	ENSP00000252321.3		P22460-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000207

AC:

AN:

250716

AF XY:

0.000162

show subpopulations

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 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.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.000984

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000585

AC:

AN:

1111968

Other (OTH)

AF:

0.0000993

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41562

American (AMR)

AF:

0.000261

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000118

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.000140

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

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

Nov 08, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in association with idiopathic pulmonary hypertension; patient-specific clinical data and segregation data were not provided (PMID: 17267549); In vitro functional studies suggest that G182R may affect the KCNA5 channel function (PMID: 20018952); however, it is not clear how well these studies reproduce in vivo condition; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37201951, 36578258, 20018952, 28341588, 17267549) -

Jan 24, 2018

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:provider interpretation

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 (KCNA1â€“7, KCNA10, KCNB1â€“2, KCNC1â€“4, and KCND1â€“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 â€œOtherâ€ 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 patientâ€™s Latino ancestryâ€”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:1Benign:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 05, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.57

MutationAssessor

Pathogenic

3.9

PhyloP100

9.9

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.95

MutPred

0.95

Gain of solvent accessibility (P = 0.0171);

MVP

0.98

MPC

1.6

ClinPred

0.61

GERP RS

4.7

Varity_R

0.86

gMVP

0.92

Mutation Taster

=31/69

disease causing

(source)

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

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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