rs12720442

chr12-5044898-G-Achr12-5044898-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002234.4(KCNA5):c.751G>A(p.Ala251Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0135 in 1,613,840 control chromosomes in the GnomAD database, including 216 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 32)
  • Exomes 𝑓: 0.014 (188 hom.)
• Consequence: KCNA5 NM_002234.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.67

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004824847).
• BP6: Variant 12-5044898-G-A is Benign according to our data. Variant chr12-5044898-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 191570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5044898-G-A is described in Lovd as [Benign]. Variant chr12-5044898-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0112 (1706/152100) while in subpopulation AMR AF= 0.0344 (526/15294). AF 95% confidence interval is 0.032. There are 28 homozygotes in gnomad4. There are 868 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1705 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNA5	NM_002234.4	c.751G>A	p.Ala251Thr	missense_variant	1/1	ENST00000252321.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNA5	ENST00000252321.5	c.751G>A	p.Ala251Thr	missense_variant	1/1		NM_002234.4	P1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1705 AN: 151982 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0344

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00851

Gnomad FIN AF: 0.00943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.0144 AC: 3627 AN: 251108 Hom.: 55 AF XY: 0.0134 AC XY: 1816 AN XY: 135774

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.0456

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00702

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0137 AC: 20070 AN: 1461740 Hom.: 188 Cov.: 32 AF XY: 0.0133 AC XY: 9690 AN XY: 727178

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.0433

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00815

Gnomad4 FIN exome AF: 0.0108

Gnomad4 NFE exome AF: 0.0143

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0112 AC: 1706 AN: 152100 Hom.: 28 Cov.: 32 AF XY: 0.0117 AC XY: 868 AN XY: 74340

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.0344

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00852

Gnomad4 FIN AF: 0.00943

Gnomad4 NFE AF: 0.0134

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00969 Hom.: 6

Bravo AF: 0.0118

TwinsUK AF: 0.0186 AC: 69

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0127 AC: 109

ExAC AF: 0.0131 AC: 1589

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0133

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
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+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Atrial fibrillation, familial, 7 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.011
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.90	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.080
Sift	Benign	0.081	T
Sift4G	Benign	0.39	T
Polyphen		0.0070	B
Vest4		0.27
MPC		0.62
ClinPred		0.0057	T
GERP RS		4.8
Varity_R		0.11
gMVP		0.73

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: rs12720442; hg19: chr12-5154064; COSMIC: COSV52908588;