rs139805781

Positions:

chr12-5045877-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002234.4(KCNA5):c.1730G>A(p.Arg577Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

KCNA5
NM_002234.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 1.08

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.099464566).

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA5	NM_002234.4 linkuse as main transcript	c.1730G>A	p.Arg577Gln	missense_variant	1/1	ENST00000252321.5	NP_002225.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNA5	ENST00000252321.5 linkuse as main transcript	c.1730G>A	p.Arg577Gln	missense_variant	1/1		NM_002234.4	ENSP00000252321	P1	P22460-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000558

AC:

AN:

250970

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.000741

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461792

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000314

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000403

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Atrial fibrillation, familial, 7

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 06, 2022	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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 537311). This variant has not been reported in the literature in individuals affected with KCNA5-related conditions. This variant is present in population databases (rs139805781, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 577 of the KCNA5 protein (p.Arg577Gln). -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 18, 2021	- -

Pulmonary arterial hypertension

Benign:1

Likely benign, no assertion criteria provided

clinical testing

John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine

Sep 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.22

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.099

MetaSVM

Uncertain

0.25

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

0.19

REVEL

Benign

0.17

Sift

Benign

0.048

Sift4G

Benign

0.18

Polyphen

0.019

Vest4

0.10

MVP

1.0

MPC

0.61

ClinPred

0.020

GERP RS

3.0

Varity_R

0.047

gMVP

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over