chr9-135792141-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_020822.3(KCNT1):​c.3688C>T​(p.Arg1230Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,453,622 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1230H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

KCNT1
NM_020822.3 missense

Scores

3
7
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.93

Publications

0 publications found
Variant links:
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 syndrome
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • developmental and epileptic encephalopathy, 14
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
  • malignant migrating partial seizures of infancy
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
  • autosomal dominant nocturnal frontal lobe epilepsy 5
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • autosomal dominant nocturnal frontal lobe epilepsy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2
High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNT1NM_020822.3 linkc.3688C>T p.Arg1230Cys missense_variant Exon 31 of 31 ENST00000371757.7 NP_065873.2 Q5JUK3-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNT1ENST00000371757.7 linkc.3688C>T p.Arg1230Cys missense_variant Exon 31 of 31 1 NM_020822.3 ENSP00000360822.2 Q5JUK3-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.0000208
AC:
5
AN:
240888
AF XY:
0.00000761
show subpopulations
Gnomad AFR exome
AF:
0.0000636
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000181
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000165
AC:
24
AN:
1453622
Hom.:
0
Cov.:
32
AF XY:
0.0000152
AC XY:
11
AN XY:
723374
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33454
American (AMR)
AF:
0.00
AC:
0
AN:
44616
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26080
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39658
South Asian (SAS)
AF:
0.0000465
AC:
4
AN:
86010
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
46190
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000171
AC:
19
AN:
1111566
Other (OTH)
AF:
0.00
AC:
0
AN:
60282
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.494
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 Uncertain:1
Jan 11, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 572792). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals affected with KCNT1-related conditions. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1230 of the KCNT1 protein (p.Arg1230Cys). This variant is present in population databases (rs771068120, gnomAD 0.007%). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Benign
-0.030
T
BayesDel_noAF
Benign
-0.10
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.23
.;.;.;.;.;.;.;.;T;.
Eigen
Benign
0.098
Eigen_PC
Benign
-0.070
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Uncertain
0.54
D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
1.5
.;.;.;.;.;.;.;.;L;.
PhyloP100
1.9
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-2.4
.;.;N;.;.;.;.;.;.;N
REVEL
Uncertain
0.36
Sift
Pathogenic
0.0
.;.;D;.;.;.;.;.;.;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D;D;D;D
Vest4
0.70
MVP
0.57
MPC
0.49
ClinPred
0.38
T
GERP RS
2.7
Varity_R
0.27
gMVP
0.46
Mutation Taster
=72/28
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs771068120; hg19: chr9-138683987; API