12-5044898-G-A

Position:

chr12-5044898-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 13/20 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.67

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1706 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA5	NM_002234.4 linkuse as main transcript	c.751G>A	p.Ala251Thr	missense_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.751G>A	p.Ala251Thr	missense_variant	1/1		NM_002234.4	ENSP00000252321	P1	P22460-1

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1705

AN:

151982

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0134

AC XY:

1816

AN XY:

135774

show subpopulations

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.:

AF XY:

0.0133

AC XY:

9690

AN XY:

727178

show subpopulations

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.:

Cov.:

AF XY:

0.0117

AC XY:

868

AN XY:

74340

show subpopulations

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.:

Bravo

AF:

0.0118

TwinsUK

AF:

0.0186

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0127

AC:

109

ExAC

AF:

0.0131

AC:

1589

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0119

EpiControl

AF:

0.0133

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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 -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2024	- -

Atrial fibrillation, familial, 7

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 06, 2020	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:3

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)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Benign

-0.011

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0048

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.3

MutationTaster

Benign

0.90

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.4

REVEL

Benign

0.080

Sift

Benign

0.081

Sift4G

Benign

0.39

Polyphen

0.0070

Vest4

0.27

MPC

0.62

ClinPred

0.0057

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

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