rs745760298

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002234.4(KCNA5):ā€‹c.911T>Cā€‹(p.Met304Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000959 in 1,460,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000096 ( 0 hom. )

Consequence

KCNA5
NM_002234.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0750
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.109929144).
BS2
High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNA5NM_002234.4 linkuse as main transcriptc.911T>C p.Met304Thr missense_variant 1/1 ENST00000252321.5 NP_002225.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNA5ENST00000252321.5 linkuse as main transcriptc.911T>C p.Met304Thr missense_variant 1/1 NM_002234.4 ENSP00000252321 P1P22460-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000811
AC:
2
AN:
246516
Hom.:
0
AF XY:
0.0000149
AC XY:
2
AN XY:
133880
show subpopulations
Gnomad AFR exome
AF:
0.0000632
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000905
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000959
AC:
14
AN:
1460228
Hom.:
0
Cov.:
32
AF XY:
0.00000964
AC XY:
7
AN XY:
726322
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000900
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
ExAC
AF:
0.00000825
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Atrial fibrillation, familial, 7 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 08, 2022This variant is present in population databases (rs745760298, gnomAD 0.0009%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 304 of the KCNA5 protein (p.Met304Thr). This variant has not been reported in the literature in individuals affected with KCNA5-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 469602). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.056
BayesDel_addAF
Uncertain
0.041
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
0.54
DANN
Benign
0.19
DEOGEN2
Uncertain
0.45
T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.033
N
LIST_S2
Benign
0.11
T
M_CAP
Benign
0.082
D
MetaRNN
Benign
0.11
T
MetaSVM
Uncertain
0.077
D
MutationAssessor
Benign
0.34
N
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
0.18
N
REVEL
Uncertain
0.30
Sift
Benign
0.44
T
Sift4G
Benign
0.41
T
Polyphen
0.0
B
Vest4
0.036
MVP
0.96
MPC
0.61
ClinPred
0.051
T
GERP RS
-3.9
Varity_R
0.055
gMVP
0.64

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.

Other links and lift over

dbSNP: rs745760298; hg19: chr12-5154224; API