rs71537801

chr12-5044407-G-Achr12-5044407-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002234.4(KCNA5):c.260G>A(p.Arg87Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,594,464 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: KCNA5 NM_002234.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.0260

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016324699).
• BS2: High AC in GnomAd at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNA5	NM_002234.4	c.260G>A	p.Arg87Gln	missense_variant	1/1	ENST00000252321.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNA5	ENST00000252321.5	c.260G>A	p.Arg87Gln	missense_variant	1/1		NM_002234.4	P1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000327 AC: 70 AN: 214262 Hom.: 0 AF XY: 0.000379 AC XY: 45 AN XY: 118770

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000307

Gnomad ASJ exome AF: 0.000217

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000352

Gnomad FIN exome AF: 0.0000697

Gnomad NFE exome AF: 0.000535

Gnomad OTH exome AF: 0.000924

GnomAD4 exome AF: 0.000234 AC: 337 AN: 1442108 Hom.: 0 Cov.: 31 AF XY: 0.000237 AC XY: 170 AN XY: 716816

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000347

Gnomad4 ASJ exome AF: 0.000350

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000355

Gnomad4 FIN exome AF: 0.0000447

Gnomad4 NFE exome AF: 0.000258

Gnomad4 OTH exome AF: 0.000285

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74494

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000287 Hom.: 0

Bravo AF: 0.000189

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000594 AC: 5

ExAC AF: 0.000259 AC: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atrial fibrillation, familial, 7 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 21, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 87 of the KCNA5 protein (p.Arg87Gln). This variant is present in population databases (rs71537801, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with atrial fibrillation and Brugada syndrome (PMID: 18209767, 26220970). ClinVar contains an entry for this variant (Variation ID: 565628). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects KCNA5 function (PMID: 16411137). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 14, 2022

Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#565628); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In vitro functional studies in CHO cells suggest the R87Q variant may impact channel function, however, it is not reproduced when expressed in the HEK 293 cells (Plante et al., 2006); additional studies are needed to clarify the functional effect of this variant in vivo; This variant is associated with the following publications: (PMID: 16411137, 26220970, 18209767, 27535533, 26582918) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	0.50
Dann	Benign	0.93
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	-0.42	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.28
Sift	Benign	1.0	T
Sift4G	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.91
MPC		0.61
ClinPred		0.016	T
GERP RS		-2.3
Varity_R		0.027
gMVP		0.26

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: rs71537801; hg19: chr12-5153573;