rs745965148
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP3BS2
The NM_020822.3(KCNT1):c.1250G>A(p.Arg417His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
KCNT1
NM_020822.3 missense
NM_020822.3 missense
Scores
6
8
5
Clinical Significance
Conservation
PhyloP100: 7.83
Genes affected
KCNT1 (HGNC:18865): (potassium sodium-activated channel subfamily T member 1) Potassium 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. This gene encodes a sodium-activated potassium channel subunit which is thought to function in ion conductance and developmental signaling pathways. Mutations in this gene cause the early-onset epileptic disorders, malignant migrating partial seizures of infancy and autosomal dominant nocturnal frontal lobe epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.831
BS2
High AC in GnomAdExome4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNT1 | NM_020822.3 | c.1250G>A | p.Arg417His | missense_variant | 13/31 | ENST00000371757.7 | NP_065873.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNT1 | ENST00000371757.7 | c.1250G>A | p.Arg417His | missense_variant | 13/31 | 1 | NM_020822.3 | ENSP00000360822.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000818 AC: 2AN: 244434Hom.: 0 AF XY: 0.0000151 AC XY: 2AN XY: 132464
GnomAD3 exomes
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2
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GnomAD4 exome AF: 0.00000343 AC: 5AN: 1458026Hom.: 0 Cov.: 33 AF XY: 0.00000414 AC XY: 3AN XY: 724930
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724930
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ExAC
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3
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 07, 2020 | In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is present in population databases (rs745965148, ExAC <0.01%) but has not been reported in the literature in individuals with a KCNT1-related disease. This sequence change replaces arginine with histidine at codon 417 of the KCNT1 protein (p.Arg417His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. - |
Developmental and epileptic encephalopathy, 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Oct 22, 2020 | - - |
Autosomal dominant nocturnal frontal lobe epilepsy 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
.;.;.;.;.;.;.;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;.;.;.;.;.;.;L;.
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
.;.;D;D;.;.;.;.;D;D
REVEL
Uncertain
Sift
Uncertain
.;.;D;D;.;.;.;.;T;T
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D
Polyphen
0.90
.;.;.;.;.;.;.;.;P;.
Vest4
MutPred
0.47
.;.;.;.;.;.;Loss of MoRF binding (P = 0.0447);Loss of MoRF binding (P = 0.0447);Loss of MoRF binding (P = 0.0447);Loss of MoRF binding (P = 0.0447);
MVP
MPC
1.1
ClinPred
D
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