rs376758763
Positions:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_020822.3(KCNT1):c.2527G>A(p.Asp843Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000941 in 1,550,890 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000093 ( 0 hom. )
Consequence
KCNT1
NM_020822.3 missense
NM_020822.3 missense
Scores
1
7
11
Clinical Significance
Conservation
PhyloP100: 9.65
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 Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.201121).
BP6
Variant 9-135778428-G-A is Benign according to our data. Variant chr9-135778428-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 833602.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 16 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNT1 | NM_020822.3 | c.2527G>A | p.Asp843Asn | missense_variant | 22/31 | ENST00000371757.7 | NP_065873.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNT1 | ENST00000371757.7 | c.2527G>A | p.Asp843Asn | missense_variant | 22/31 | 1 | NM_020822.3 | ENSP00000360822 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152178Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000897 AC: 14AN: 156076Hom.: 0 AF XY: 0.0000609 AC XY: 5AN XY: 82164
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GnomAD4 exome AF: 0.0000929 AC: 130AN: 1398712Hom.: 0 Cov.: 32 AF XY: 0.0000884 AC XY: 61AN XY: 689878
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GnomAD4 genome AF: 0.000105 AC: 16AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74330
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 19, 2020 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 10, 2023 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 16, 2024 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;.;.;.;.;.;.;.;T;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;.;.;.;.;.;.;L;.
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;.;D;.;.;.;.;.;N;N
REVEL
Uncertain
Sift
Benign
.;.;T;.;.;.;.;.;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T;T;T
Polyphen
0.17
.;.;.;.;.;.;.;.;B;.
Vest4
MVP
MPC
0.64
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at