12-5044528-C-T

Position:

chr12-5044528-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_002234.4(KCNA5):c.381C>T(p.Ser127=) 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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 309336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5044528-C-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4196 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA5	NM_002234.4 linkuse as main transcript	c.381C>T	p.Ser127=	synonymous_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.381C>T	p.Ser127=	synonymous_variant	1/1		NM_002234.4	ENSP00000252321	P1	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

GnomAD3 exomes

AF:

0.0258

AC:

6448

AN:

249732

Hom.:

115

AF XY:

0.0260

AC XY:

3514

AN XY:

135328

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 SAS exome

AF:

0.0125

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

Gnomad4 AFR exome

AF:

0.00588

Gnomad4 AMR exome

AF:

0.0126

Gnomad4 ASJ exome

AF:

0.0234

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0127

Gnomad4 FIN exome

AF:

0.0290

Gnomad4 NFE exome

AF:

0.0476

Gnomad4 OTH exome

AF:

0.0356

GnomAD4 genome

AF:

0.0275

AC:

4196

AN:

152312

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1885

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00750

Gnomad4 AMR

AF:

0.0182

Gnomad4 ASJ

AF:

0.0213

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.0110

Gnomad4 FIN

AF:

0.0320

Gnomad4 NFE

AF:

0.0445

Gnomad4 OTH

AF:

0.0251

Alfa

AF:

0.0376

Hom.:

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2023	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. -

Atrial fibrillation, familial, 7

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 30, 2023	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2020	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

DANN

Benign

0.91

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