rs199794307
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_002234.4(KCNA5):c.913G>A(p.Ala305Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,612,298 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000073 ( 0 hom. )
Consequence
KCNA5
NM_002234.4 missense
NM_002234.4 missense
Scores
1
7
11
Clinical Significance
Conservation
PhyloP100: 1.59
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
?
High AC in GnomAd4 at 10 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNA5 | NM_002234.4 | c.913G>A | p.Ala305Thr | missense_variant | 1/1 | ENST00000252321.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNA5 | ENST00000252321.5 | c.913G>A | p.Ala305Thr | missense_variant | 1/1 | NM_002234.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000658 AC: 10AN: 152040Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
10
AN:
152040
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000243 AC: 6AN: 246488Hom.: 0 AF XY: 0.0000373 AC XY: 5AN XY: 133882
GnomAD3 exomes
AF:
AC:
6
AN:
246488
Hom.:
AF XY:
AC XY:
5
AN XY:
133882
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000726 AC: 106AN: 1460258Hom.: 0 Cov.: 32 AF XY: 0.0000688 AC XY: 50AN XY: 726356
GnomAD4 exome
AF:
AC:
106
AN:
1460258
Hom.:
Cov.:
32
AF XY:
AC XY:
50
AN XY:
726356
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000658 AC: 10AN: 152040Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74240
GnomAD4 genome
?
AF:
AC:
10
AN:
152040
Hom.:
Cov.:
32
AF XY:
AC XY:
8
AN XY:
74240
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
?
AF:
AC:
1
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Atrial fibrillation, familial, 7 Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 01, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects KCNA5 function (PMID: 23264583, 28803858). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 127136). This missense change has been observed in individual(s) with atrial fibrillation (PMID: 23264583, 24144883). This variant is present in population databases (rs199794307, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 305 of the KCNA5 protein (p.Ala305Thr). - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2016 | - - |
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
T
MutationAssessor
Benign
N
MutationTaster
Benign
N
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of glycosylation at A305 (P = 0.002);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at