rs17215409

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002234.4(KCNA5):c.919C>T(p.Pro307Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,612,682 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 7 hom. )

Consequence

KCNA5
NM_002234.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 0.293

Publications

5 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010886967).

BP6

Variant 12-5045066-C-T is Benign according to our data. Variant chr12-5045066-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191463.

BS2

High AC in GnomAd4 at 354 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002234.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA5	NM_002234.4	MANE Select	c.919C>T	p.Pro307Ser	missense	Exon 1 of 1	NP_002225.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA5	ENST00000252321.5	TSL:6 MANE Select	c.919C>T	p.Pro307Ser	missense	Exon 1 of 1	ENSP00000252321.3

Frequencies

GnomAD3 genomes

AF:

0.00233

AC:

355

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00410

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00218

AC:

539

AN:

247016

AF XY:

0.00236

show subpopulations

Gnomad AFR exome

AF:

0.000942

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.000201

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00104

Gnomad NFE exome

AF:

0.00399

Gnomad OTH exome

AF:

0.00214

GnomAD4 exome

AF:

0.00340

AC:

4971

AN:

1460472

Hom.:

Cov.:

AF XY:

0.00339

AC XY:

2461

AN XY:

726440

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33458

American (AMR)

AF:

0.00143

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.000537

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.000186

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

52840

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00420

AC:

4671

AN:

1111490

Other (OTH)

AF:

0.00224

AC:

135

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

343

685

1028

1370

1713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

170

340

510

680

850

<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:

0.00233

AC:

354

AN:

152210

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000938

AC:

AN:

41558

American (AMR)

AF:

0.00131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000866

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00410

AC:

279

AN:

68006

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00331

Hom.:

Bravo

AF:

0.00226

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00190

AC:

230

EpiCase

AF:

0.00463

EpiControl

AF:

0.00492

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Atrial fibrillation, familial, 7 (2)

not specified (2)

altered potassium channel function (1)

KCNA5-related disorder (1)

Pulmonary arterial hypertension (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

3.3

(source)

DANN

Benign

0.61

DEOGEN2

Uncertain

0.47

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.44

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

1.0

PhyloP100

0.29

PrimateAI

Benign

0.45

PROVEAN

Benign

0.020

REVEL

Benign

0.21

Sift

Benign

0.45

Sift4G

Benign

0.87

Polyphen

0.0010

Vest4

0.081

MVP

0.98

MPC

0.53

ClinPred

0.0022

GERP RS

-0.86

Varity_R

0.024

gMVP

0.63

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over