rs886041691
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3PM2PP3PP5_Very_Strong
The NM_020822.3(KCNT1):c.1546A>G(p.Met516Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003441324: Experimental studies have shown that this missense change affects KCNT1 function (PMID:26784557).".
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
KCNT1
NM_020822.3 missense
NM_020822.3 missense
Scores
2
4
12
Clinical Significance
Conservation
PhyloP100: 3.55
Publications
12 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
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 15 ACMG points.
PS3
PS3 evidence extracted from ClinVar submissions: SCV003441324: Experimental studies have shown that this missense change affects KCNT1 function (PMID: 26784557).
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.772
PP5
Variant 9-135769982-A-G is Pathogenic according to our data. Variant chr9-135769982-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 280499.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.1546A>G | p.Met516Val | missense | Exon 16 of 31 | ENSP00000360822.2 | Q5JUK3-3 | ||
| KCNT1 | TSL:1 | n.*1156A>G | non_coding_transcript_exon | Exon 16 of 32 | ENSP00000418777.1 | F8WC49 | |||
| KCNT1 | TSL:1 | n.*1156A>G | 3_prime_UTR | Exon 16 of 32 | ENSP00000418777.1 | F8WC49 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
34
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1404376Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 693328
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1404376
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
693328
African (AFR)
AF:
AC:
0
AN:
31898
American (AMR)
AF:
AC:
0
AN:
36878
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25194
East Asian (EAS)
AF:
AC:
0
AN:
36238
South Asian (SAS)
AF:
AC:
0
AN:
79542
European-Finnish (FIN)
AF:
AC:
0
AN:
48776
Middle Eastern (MID)
AF:
AC:
0
AN:
5310
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1082366
Other (OTH)
AF:
AC:
0
AN:
58174
GnomAD4 genome
GnomAD4 genome
Cov.:
34
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
2
-
-
Developmental and epileptic encephalopathy, 14 (2)
1
-
-
Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)
1
-
-
Malignant migrating partial seizures of infancy (1)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Benign
L
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MutPred
Gain of ubiquitination at K494 (P = 0.078)
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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