rs200137341

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_020822.3(KCNT1):ā€‹c.146C>Gā€‹(p.Thr49Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000058 in 1,447,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000040 ( 0 hom., cov: 32)
Exomes š‘“: 0.000060 ( 0 hom. )

Consequence

KCNT1
NM_020822.3 missense

Scores

2
14

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.76
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 Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0130446255).
BP6
Variant 9-135714612-C-G is Benign according to our data. Variant chr9-135714612-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 386452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNT1NM_020822.3 linkuse as main transcriptc.146C>G p.Thr49Ser missense_variant 2/31 ENST00000371757.7 NP_065873.2
KCNT1XM_011518878.4 linkuse as main transcriptc.281C>G p.Thr94Ser missense_variant 2/31 XP_011517180.1
KCNT1XM_011518879.4 linkuse as main transcriptc.281C>G p.Thr94Ser missense_variant 2/31 XP_011517181.1
KCNT1NM_001272003.2 linkuse as main transcriptc.110+12244C>G intron_variant NP_001258932.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNT1ENST00000371757.7 linkuse as main transcriptc.146C>G p.Thr49Ser missense_variant 2/311 NM_020822.3 ENSP00000360822 A2Q5JUK3-3

Frequencies

GnomAD3 genomes
AF:
0.0000400
AC:
6
AN:
149844
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000663
Gnomad ASJ
AF:
0.00116
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000149
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000150
AC:
26
AN:
173776
Hom.:
0
AF XY:
0.000173
AC XY:
17
AN XY:
98544
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00297
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000254
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000601
AC:
78
AN:
1297880
Hom.:
0
Cov.:
30
AF XY:
0.0000650
AC XY:
42
AN XY:
645764
show subpopulations
Gnomad4 AFR exome
AF:
0.000308
Gnomad4 AMR exome
AF:
0.0000600
Gnomad4 ASJ exome
AF:
0.00220
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000147
Gnomad4 OTH exome
AF:
0.000140
GnomAD4 genome
AF:
0.0000400
AC:
6
AN:
149844
Hom.:
0
Cov.:
32
AF XY:
0.0000410
AC XY:
3
AN XY:
73084
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000663
Gnomad4 ASJ
AF:
0.00116
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000149
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000653
Hom.:
0
ExAC
AF:
0.0000928
AC:
11

ClinVar

Significance: Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 26, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 09, 2023- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 16, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Developmental and epileptic encephalopathy, 14 Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabMar 15, 2022- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2023KCNT1: BS1 -
Autosomal dominant nocturnal frontal lobe epilepsy 5 Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabMar 15, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
13
DANN
Benign
0.91
Eigen
Benign
-0.77
Eigen_PC
Benign
-0.68
FATHMM_MKL
Benign
0.19
N
LIST_S2
Benign
0.32
T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.013
T;T
MetaSVM
Benign
-0.99
T
MutationTaster
Benign
1.0
D;D;N;N
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-0.20
.;N
REVEL
Benign
0.078
Sift
Benign
0.085
.;T
Sift4G
Benign
0.10
T;T
Vest4
0.066
MutPred
0.24
Gain of disorder (P = 0.055);Gain of disorder (P = 0.055);
MVP
0.15
MPC
0.57
ClinPred
0.12
T
GERP RS
1.3
gMVP
0.13

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs200137341; hg19: chr9-138606458; API