rs948125814
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_001378969.1(KCND3):āc.1849A>Gā(p.Ile617Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000383 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.000038 ( 0 hom. )
Consequence
KCND3
NM_001378969.1 missense
NM_001378969.1 missense
Scores
2
8
6
Clinical Significance
Conservation
PhyloP100: 3.04
Genes affected
KCND3 (HGNC:6239): (potassium voltage-gated channel subfamily D member 3) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion 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, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member includes two isoforms with different sizes, which are encoded by alternatively spliced transcript variants of this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, KCND3
BP4
?
Computational evidence support a benign effect (MetaRNN=0.21625903).
BS2
?
High AC in GnomAdExome4 at 56 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCND3 | NM_001378969.1 | c.1849A>G | p.Ile617Val | missense_variant | 8/8 | ENST00000302127.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCND3 | ENST00000302127.5 | c.1849A>G | p.Ile617Val | missense_variant | 8/8 | 5 | NM_001378969.1 | P3 | |
KCND3 | ENST00000315987.6 | c.1849A>G | p.Ile617Val | missense_variant | 8/8 | 1 | P3 | ||
KCND3 | ENST00000369697.5 | c.1792A>G | p.Ile598Val | missense_variant | 6/6 | 1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251324Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135826
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GnomAD4 exome AF: 0.0000383 AC: 56AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 727248
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 29, 2020 | The p.I617V variant (also known as c.1849A>G), located in coding exon 7 of the KCND3 gene, results from an A to G substitution at nucleotide position 1849. The isoleucine at codon 617 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Spinocerebellar ataxia type 19/22 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 19, 2022 | 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: 533723). This variant has not been reported in the literature in individuals affected with KCND3-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 617 of the KCND3 protein (p.Ile617Val). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Benign
T;T;T
Polyphen
0.50
.;P;.
Vest4
MutPred
0.22
.;Loss of sheet (P = 7e-04);.;
MVP
MPC
0.28
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at