12-5044528-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_002234.4(KCNA5):c.381C>T(p.Ser127Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 1,613,564 control chromosomes in the GnomAD database, including 1,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 80 hom., cov: 33)

Exomes 𝑓: 0.040 ( 1393 hom. )

Consequence

KCNA5
NM_002234.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -9.04

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 12-5044528-C-T is Benign according to our data. Variant chr12-5044528-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 309336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-9.04 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0275 (4196/152312) while in subpopulation NFE AF = 0.0445 (3027/68020). AF 95% confidence interval is 0.0432. There are 80 homozygotes in GnomAd4. There are 1885 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 4196 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA5	NM_002234.4 link	c.381C>T	p.Ser127Ser	synonymous_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.381C>T	p.Ser127Ser	synonymous_variant	Exon 1 of 1	6	NM_002234.4	ENSP00000252321.3		P22460-1

Frequencies

GnomAD3 genomes

AF:

0.0276

AC:

4195

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00752

Gnomad AMI

AF:

0.0615

Gnomad AMR

AF:

0.0183

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.0320

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0445

Gnomad OTH

AF:

0.0254

GnomAD2 exomes

AF:

0.0258

AC:

6448

AN:

249732

AF XY:

0.0260

show subpopulations

Gnomad AFR exome

AF:

0.00738

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.0204

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0290

Gnomad NFE exome

AF:

0.0402

Gnomad OTH exome

AF:

0.0292

GnomAD4 exome

AF:

0.0405

AC:

59166

AN:

1461252

Hom.:

1393

Cov.:

AF XY:

0.0396

AC XY:

28755

AN XY:

726916

show subpopulations

African (AFR)

AF:

0.00588

AC:

197

AN:

33480

American (AMR)

AF:

0.0126

AC:

565

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0234

AC:

611

AN:

26092

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0127

AC:

1092

AN:

86214

European-Finnish (FIN)

AF:

0.0290

AC:

1539

AN:

53058

Middle Eastern (MID)

AF:

0.00659

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0476

AC:

52972

AN:

1111856

Other (OTH)

AF:

0.0356

AC:

2151

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

3840

7679

11519

15358

19198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1988

3976

5964

7952

9940

<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:

0.0275

AC:

4196

AN:

152312

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1885

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00750

AC:

312

AN:

41590

American (AMR)

AF:

0.0182

AC:

279

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3468

East Asian (EAS)

AF:

0.000388

AC:

AN:

5160

South Asian (SAS)

AF:

0.0110

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0320

AC:

340

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0445

AC:

3027

AN:

68020

Other (OTH)

AF:

0.0251

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

218

437

655

874

1092

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0360

Hom.:

101

Bravo

AF:

0.0256

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0423

EpiControl

AF:

0.0337

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 05, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: KCNA5 c.381C>T alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.026 in 249732 control chromosomes in the gnomAD database, including 115 homozygotes. The observed variant frequency is approximately 275-fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNA5 causing Atrial Fibrillation phenotype (9.4e-05), strongly suggesting that the variant is benign. c.381C>T has been reported in the literature in individuals affected with Atrial Fibrillation or pulmonary arterial hypertension without evidence of causality and with other co-occurring variants (Winkel_2011, Wang_2016). These reports do not provide unequivocal conclusions about association of the variant with Atrial Fibrillation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Atrial fibrillation, familial, 7

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Sep 30, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 23, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28768485, 24068186, 15735608) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.12

(source)

DANN

Benign

0.91

PhyloP100

-9.0

Mutation Taster

=98/2

polymorphism (auto)

(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