chr12-5044226-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002234.4(KCNA5):​c.79G>T​(p.Gly27Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G27S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

KCNA5
NM_002234.4 missense

Scores

6
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.91

Publications

0 publications found
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 Gene-Disease associations (from GenCC):
  • atrial fibrillation, familial, 7
    Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • familial atrial fibrillation
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2121174).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNA5NM_002234.4 linkc.79G>T p.Gly27Cys missense_variant Exon 1 of 1 ENST00000252321.5 NP_002225.2 P22460-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNA5ENST00000252321.5 linkc.79G>T p.Gly27Cys missense_variant Exon 1 of 1 6 NM_002234.4 ENSP00000252321.3 P22460-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.22e-7
AC:
1
AN:
1385836
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
684074
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
31636
American (AMR)
AF:
0.00
AC:
0
AN:
35726
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25148
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35884
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79222
European-Finnish (FIN)
AF:
0.0000273
AC:
1
AN:
36672
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4746
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1078998
Other (OTH)
AF:
0.00
AC:
0
AN:
57804
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.089
BayesDel_addAF
Uncertain
0.058
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Benign
0.24
T
Eigen
Benign
-0.35
Eigen_PC
Benign
-0.41
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.47
T
M_CAP
Uncertain
0.27
D
MetaRNN
Benign
0.21
T
MetaSVM
Uncertain
0.36
D
MutationAssessor
Benign
0.81
L
PhyloP100
1.9
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-0.71
N
REVEL
Benign
0.29
Sift
Benign
0.096
T
Sift4G
Uncertain
0.047
D
Polyphen
0.94
P
Vest4
0.22
MutPred
0.15
Gain of sheet (P = 0.0344);
MVP
1.0
MPC
0.88
ClinPred
0.52
D
GERP RS
3.4
PromoterAI
-0.025
Neutral
Varity_R
0.15
gMVP
0.53
Mutation Taster
=92/8
polymorphism

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

Other links and lift over

dbSNP: rs201238766; hg19: chr12-5153392; API