9-135786480-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020822.3(KCNT1):​c.3461A>T​(p.Lys1154Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,430 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KCNT1
NM_020822.3 missense

Scores

2
9
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.07
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3993101).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNT1NM_020822.3 linkc.3461A>T p.Lys1154Met missense_variant Exon 29 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.3461A>T p.Lys1154Met missense_variant Exon 29 of 31 1 NM_020822.3 ENSP00000360822.2 Q5JUK3-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000447
AC:
1
AN:
223552
Hom.:
0
AF XY:
0.00000807
AC XY:
1
AN XY:
123926
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000103
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.89e-7
AC:
1
AN:
1451430
Hom.:
0
Cov.:
36
AF XY:
0.00
AC XY:
0
AN XY:
721842
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000839
AC:
1

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Nov 10, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3461A>T (p.K1154M) alteration is located in exon 29 (coding exon 29) of the KCNT1 gene. This alteration results from a A to T substitution at nucleotide position 3461, causing the lysine (K) at amino acid position 1154 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.67
BayesDel_addAF
Benign
-0.011
T
BayesDel_noAF
Benign
-0.25
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.31
.;.;.;.;.;.;.;.;T;.
Eigen
Uncertain
0.27
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.40
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.87
T
MutationAssessor
Uncertain
2.0
.;.;.;.;.;.;.;.;M;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-3.5
.;.;D;.;.;.;.;.;.;D
REVEL
Benign
0.20
Sift
Uncertain
0.0020
.;.;D;.;.;.;.;.;.;D
Sift4G
Uncertain
0.0030
D;D;D;D;D;D;D;D;D;D
Vest4
0.57
MVP
0.54
MPC
0.40
ClinPred
0.97
D
GERP RS
3.6
Varity_R
0.60
gMVP
0.60

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs779810960; hg19: chr9-138678326; API