rs397515407

Positions:

chr9-135765188-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_020822.3(KCNT1):c.1193G>A(p.Arg398Gln) 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

KCNT1
NM_020822.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 9.63

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.751

PP5

Variant 9-135765188-G-A is Pathogenic according to our data. Variant chr9-135765188-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135765188-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3 linkuse as main transcript	c.1193G>A	p.Arg398Gln	missense_variant	12/31	ENST00000371757.7	NP_065873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7 linkuse as main transcript	c.1193G>A	p.Arg398Gln	missense_variant	12/31	1	NM_020822.3	ENSP00000360822	A2	Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152074

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74266

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy 5

Pathogenic:3Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2012	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 07, 2020	- -

Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 398 of the KCNT1 protein (p.Arg398Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant nocturnal frontal lobe epilepsy (ADFLE), malignant migrating partial seizures of infancy (MMPSI), malignant migrating focal seizures of infancy (MMFSI), and focal epilepsy (PMID: 23086396, 25482562, 26122718, 26140313, 26648591). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39599). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNT1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects KCNT1 function (PMID: 24591078). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2018	- -

Developmental and epileptic encephalopathy, 14

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Aug 24, 2022	PM2, PM5, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	May 03, 2019	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2022	Published functional studies demonstrate that R398Q results in a gain of function that causes an increase in current amplitude and altered channel activation and deactivation kinetics (Milligan et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28488083, 24591078, 25482562, 23086396, 26122718, 26648591, 26140313, 31872048, 31130284, 32167590, 31216405, 29291456, 28252636, 33726816) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Sep 19, 2023	- -

Epilepsy syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Apr 25, 2021

- -

KCNT1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 13, 2023

The KCNT1 c.1193G>A variant is predicted to result in the amino acid substitution p.Arg398Gln. This variant has been reported in at least 14 individuals with KCNT1-related epilepsy (see for example, Heron et al. 2012. PubMed ID: 23086396; Kim et al. 2014. PubMed ID: 25482562; Møller et al. 2015. PubMed ID: 26122718; Allen et al. 2016. PubMed ID: 26648591; Barcia et al. 2019. PubMed ID: 31872048) and is documented to have occurred de novo in at least 3 cases (Abdelnour et al. 2018. PubMed ID: 29291456; Monies et al. 2019. PubMed ID: 31130284; Borlot et al. 2020. PubMed ID: 32167590). In vitro experimental studies suggest that this variant impacts protein function (Milligan et al. 2014. PubMed ID: 24591078). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare or absent in the general population. Taken together, this variant is interpreted as pathogenic. -

Seizure

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Jun 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.068

.;.;.;.;.;.;.;.;T;.

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.0090

MetaRNN

Pathogenic

0.75

D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

.;.;.;.;.;.;.;.;N;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.6

.;.;N;N;.;.;.;.;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.35

.;.;T;T;.;.;.;.;T;T

Sift4G

Benign

0.21

T;T;T;T;T;T;T;T;T;T

Polyphen

0.68

.;.;.;.;.;.;.;.;P;.

Vest4

0.98

MutPred

0.47

.;.;.;.;.;.;Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);

MVP

0.52

MPC

0.82

ClinPred

0.98

GERP RS

4.2

Varity_R

0.39

gMVP

0.89

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over