rs17215409

Positions:

• chr12-5045066-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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. 15/21 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.293

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 191463.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=1}. Variant chr12-5045066-C-T is described in Lovd as [Benign]. Variant chr12-5045066-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 354 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNA5	NM_002234.4	c.919C>T	p.Pro307Ser	missense_variant	1/1	ENST00000252321.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNA5	ENST00000252321.5	c.919C>T	p.Pro307Ser	missense_variant	1/1		NM_002234.4	P1

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152092 Hom.: 4 Cov.: 32

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

GnomAD3 exomes AF: 0.00218 AC: 539 AN: 247016 Hom.: 2 AF XY: 0.00236 AC XY: 316 AN XY: 134052

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 SAS exome AF: 0.000295

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.: 7 Cov.: 32 AF XY: 0.00339 AC XY: 2461 AN XY: 726440

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.000537

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00104

Gnomad4 NFE exome AF: 0.00420

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00233 AC: 354 AN: 152210 Hom.: 4 Cov.: 32 AF XY: 0.00208 AC XY: 155 AN XY: 74408

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00410

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00322 Hom.: 1

Bravo AF: 0.00226

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00190 AC: 230

EpiCase AF: 0.00463

EpiControl AF: 0.00492

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely 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	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	KCNA5: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2020	This variant is associated with the following publications: (PMID: 16411137, 24068186, 22402074, 21507821, 18209767, 15735608) -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 30, 2024	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Atrial fibrillation, familial, 7 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 05, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

altered potassium channel function Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

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

- -

KCNA5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 16, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	3.3
DANN	Benign	0.61
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.21
Sift	Benign	0.45	T
Sift4G	Benign	0.87	T
Polyphen		0.0010	B
Vest4		0.081
MVP		0.98
MPC		0.53
ClinPred		0.0022	T
GERP RS		-0.86
Varity_R		0.024
gMVP		0.63

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

Other links and lift over

dbSNP: rs17215409; hg19: chr12-5154232; COSMIC: COSV52906508;