12-5044239-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002234.4(KCNA5):c.92G>T(p.Gly31Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00304 in 1,539,188 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G31A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 65 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 46 hom. )

Consequence

KCNA5
NM_002234.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.437

Publications

3 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017237067).

BP6

Variant 12-5044239-G-T is Benign according to our data. Variant chr12-5044239-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 309332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.015 (2282/152344) while in subpopulation AFR AF = 0.0508 (2114/41588). AF 95% confidence interval is 0.049. There are 65 homozygotes in GnomAd4. There are 1108 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2282 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA5	NM_002234.4 link	c.92G>T	p.Gly31Val	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.92G>T	p.Gly31Val	missense_variant	Exon 1 of 1	6	NM_002234.4	ENSP00000252321.3		P22460-1

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2276

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0508

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00660

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.00366

AC:

496

AN:

135632

AF XY:

0.00283

show subpopulations

Gnomad AFR exome

AF:

0.0516

Gnomad AMR exome

AF:

0.00257

Gnomad ASJ exome

AF:

0.00527

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000313

Gnomad OTH exome

AF:

0.00146

GnomAD4 exome

AF:

0.00173

AC:

2404

AN:

1386844

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

1043

AN XY:

684660

show subpopulations

African (AFR)

AF:

0.0520

AC:

1649

AN:

31732

American (AMR)

AF:

0.00271

AC:

AN:

35782

Ashkenazi Jewish (ASJ)

AF:

0.00557

AC:

140

AN:

25152

East Asian (EAS)

AF:

0.00

AC:

AN:

36002

South Asian (SAS)

AF:

0.000290

AC:

AN:

79286

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36554

Middle Eastern (MID)

AF:

0.00353

AC:

AN:

4816

European-Non Finnish (NFE)

AF:

0.000230

AC:

248

AN:

1079670

Other (OTH)

AF:

0.00398

AC:

230

AN:

57850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

157

313

470

626

783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.0150

AC:

2282

AN:

152344

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1108

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0508

AC:

2114

AN:

41588

American (AMR)

AF:

0.00660

AC:

101

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68026

Other (OTH)

AF:

0.0123

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

115

230

346

461

576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00463

Hom.:

Bravo

AF:

0.0168

ESP6500AA

AF:

0.0335

AC:

129

ESP6500EA

AF:

0.000389

AC:

ExAC

AF:

0.00261

AC:

256

Asia WGS

AF:

0.00520

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Atrial fibrillation, familial, 7

Benign:3

Nov 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:3

Sep 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Apr 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pulmonary arterial hypertension

Benign:1

Sep 26, 2022

John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.21

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0017

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.55

PhyloP100

0.44

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.58

REVEL

Benign

0.24

Sift

Benign

0.066

Sift4G

Benign

0.15

Polyphen

0.099

Vest4

0.083

MVP

0.99

MPC

0.70

ClinPred

0.0037

GERP RS

-0.27

PromoterAI

-0.018

Neutral

(source)

Varity_R

0.10

gMVP

0.34

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over