9-135772868-C-CCCTGCTGCCCTGCGA
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2
The NM_020822.3(KCNT1):c.2170_2184dup(p.Pro724_Leu728dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,554,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000071 ( 0 hom. )
Consequence
KCNT1
NM_020822.3 inframe_insertion
NM_020822.3 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.439
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 -2 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_020822.3.
BS2
High AC in GnomAd4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNT1 | NM_020822.3 | c.2170_2184dup | p.Pro724_Leu728dup | inframe_insertion | 19/31 | ENST00000371757.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNT1 | ENST00000371757.7 | c.2170_2184dup | p.Pro724_Leu728dup | inframe_insertion | 19/31 | 1 | NM_020822.3 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152216Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000188 AC: 3AN: 159438Hom.: 0 AF XY: 0.0000233 AC XY: 2AN XY: 86020
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GnomAD4 exome AF: 0.00000713 AC: 10AN: 1401830Hom.: 0 Cov.: 31 AF XY: 0.00000578 AC XY: 4AN XY: 692422
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74356
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
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 | Invitae | Nov 27, 2023 | This variant, c.2170_2184dup, results in the insertion of 5 amino acid(s) of the KCNT1 protein (p.Pro724_Leu728dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs757605635, gnomAD 0.01%). This variant has been observed in individual(s) with infantile seizures (PMID: 31388363). ClinVar contains an entry for this variant (Variation ID: 429344). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 03, 2018 | The c.2170_2184dup15 variant (also known as p.P724_L728dup), located in coding exon 19 of the KCNT1 gene, results from an in-frame duplication of 15 nucleotides at nucleotide positions 2170 to 2184. This results in the duplication of 5 extra residues (PCDLL) between codons 724 and 728. These amino acid positions are well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al., PLoS ONE 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 25, 2022 | Reported in a patient in published literature with infantile seizures who also harbored another variant in the KCNT1 gene, although familial segregation information was not provided to determine if either variant occurred de novo or to determine if the variants occurred on the same (in cis) or on different (in trans) chromosomes (Passey et al., 2019); Not observed in large population cohorts (gnomAD); In-frame insertion of 5 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 31388363) - |
Developmental and epileptic encephalopathy, 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
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
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at