rs397515407
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_020822.3(KCNT1):c.1193G>A(p.Arg398Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R398W) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Failed GnomAD Quality Control
Consequence
KCNT1
NM_020822.3 missense
NM_020822.3 missense
Scores
3
7
8
Clinical Significance
Conservation
PhyloP100: 9.63
Publications
36 publications found
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]
KCNT1 Gene-Disease associations (from GenCC):
- childhood-onset epilepsy syndromeInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- developmental and epileptic encephalopathy, 14Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
- malignant migrating partial seizures of infancyInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
- autosomal dominant nocturnal frontal lobe epilepsy 5Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- autosomal dominant nocturnal frontal lobe epilepsyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.751
PP5
Variant 9-135765188-G-A is Pathogenic according to our data. Variant chr9-135765188-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_020822.3. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| KCNT1 | TSL:1 MANE Select | c.1193G>A | p.Arg398Gln | missense | Exon 12 of 31 | ENSP00000360822.2 | Q5JUK3-3 | ||
| KCNT1 | TSL:1 | n.*803G>A | non_coding_transcript_exon | Exon 12 of 32 | ENSP00000418777.1 | F8WC49 | |||
| KCNT1 | TSL:1 | n.*803G>A | 3_prime_UTR | Exon 12 of 32 | ENSP00000418777.1 | F8WC49 |
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 152074Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
0
AN:
152074
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
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Gnomad AMR
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Gnomad ASJ
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Gnomad SAS
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Gnomad NFE
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Gnomad OTH
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GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome 0.00 AC: 0AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74266
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
152074
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74266
African (AFR)
AF:
AC:
0
AN:
41390
American (AMR)
AF:
AC:
0
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5188
South Asian (SAS)
AF:
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
AC:
0
AN:
10600
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68016
Other (OTH)
AF:
AC:
0
AN:
2088
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
5
-
-
Developmental and epileptic encephalopathy, 14 (5)
3
-
-
Autosomal dominant nocturnal frontal lobe epilepsy 5 (4)
3
-
-
Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 (3)
2
-
-
not provided (2)
1
-
-
Childhood-onset epilepsy syndrome (1)
1
-
-
Epilepsy syndrome (1)
1
-
-
KCNT1-related disorder (1)
1
-
-
Seizure (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Benign
N
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Loss of helix (P = 0.0237)
MVP
MPC
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
Publications
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