NM_020822.3:c.2849G>A
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5
The NM_020822.3(KCNT1):c.2849G>A(p.Arg950Gln) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R950L) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
KCNT1
NM_020822.3 missense
NM_020822.3 missense
Scores
3
14
1
Clinical Significance
Conservation
PhyloP100: 9.68
Publications
22 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: Likely_pathogenic. The variant received 8 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_020822.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-135784031-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 473378.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.833
PP5
Variant 9-135784031-G-A is Pathogenic according to our data. Variant chr9-135784031-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286710.
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.2849G>A | p.Arg950Gln | missense | Exon 25 of 31 | ENSP00000360822.2 | Q5JUK3-3 | ||
| KCNT1 | TSL:1 | n.*2459G>A | non_coding_transcript_exon | Exon 25 of 32 | ENSP00000418777.1 | F8WC49 | |||
| KCNT1 | TSL:1 | n.*2459G>A | 3_prime_UTR | Exon 25 of 32 | ENSP00000418777.1 | F8WC49 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1454204Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 723792
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1454204
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
723792
African (AFR)
AF:
AC:
0
AN:
33476
American (AMR)
AF:
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39694
South Asian (SAS)
AF:
AC:
0
AN:
86248
European-Finnish (FIN)
AF:
AC:
0
AN:
45974
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111850
Other (OTH)
AF:
AC:
0
AN:
60342
GnomAD4 genome
GnomAD4 genome
Cov.:
33
EpiCase
AF:
EpiControl
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
Pathogenic
VUS
Benign
Condition
3
-
-
Developmental and epileptic encephalopathy, 14 (3)
2
1
-
not provided (3)
1
-
-
Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)
1
-
-
Inborn genetic diseases (1)
1
-
-
Seizure (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of MoRF binding (P = 0.1822)
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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