rs200694691

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_020822.3(KCNT1):c.2882G>A(p.Arg961His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KCNT1
NM_020822.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:6

Conservation

PhyloP100: 9.68

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.849

PP5

Variant 9-135784064-G-A is Pathogenic according to our data. Variant chr9-135784064-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129360.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=6, Likely_pathogenic=2}. Variant chr9-135784064-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3 link	c.2882G>A	p.Arg961His	missense_variant	25/31	ENST00000371757.7	NP_065873.2	Q5JUK3-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7 link	c.2882G>A	p.Arg961His	missense_variant	25/31	1	NM_020822.3	ENSP00000360822.2		Q5JUK3-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1452576

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723006

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2023	Identified in an individual with epileptic encephalopathy who inherited the variant from a parent; however, clinical information about the parent was not provided (PMID: 29186148); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30234941, 35940594, 35116000, 32167590, 31054119, 34114611, 36499459, 29186148, 34537872) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 24, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 09, 2013	- -

Developmental and epileptic encephalopathy, 14

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 09, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 17, 2022	Despite strong evidence for its pathogenicity, this variant has to be classified as of unknown significance, according to the ACMG-criteria (Richards et al., 2015)_x000D_ Criteria applied: PS4_MOD, PM2_SUP, PP3 -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 961 of the KCNT1 protein (p.Arg961His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KCNT1-related conditions (PMID: 29186148, 34114611; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 129360). 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%. For these reasons, this variant has been classified as Pathogenic. -

Autosomal dominant nocturnal frontal lobe epilepsy 5

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The KCNT1 missense c.2882G>A variant has been reported in individuals affected with Epilepsy nocturnal frontal lobe, 5 (Borlot F et. al., 2020; Zhu X et. al., 2017) and it has been observed de novo in at least one of these individuals. This variant has been reported to the ClinVar database as Conflicting interpretations of pathogenicity (Likely pathogenic and Variant of uncertain significance). The p.Arg961His variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Arg at position 961 is changed to a His changing protein sequence and it might alter its composition and physicochemical properties. The variant is predicted to be damaging by PolyPhen2 and the residue is conserved across species. The amino acid change p.Arg961His in KCNT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The currently available evidence indicates that the variant is Pathogenic, but additional data are needed to prove that conclusively. For these reasons, this variant has been classified as Likely Pathogenic. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2017

The p.R961H variant (also known as c.2882G>A), located in coding exon 25 of the KCNT1 gene, results from a G to A substitution at nucleotide position 2882. The arginine at codon 961 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Focal epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neurogenetics Laboratory - MEYER, AOU Meyer

Nov 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

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

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

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

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.85

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

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

1.8

.;.;.;.;.;.;.;.;L;.

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-4.3

.;.;D;.;.;.;.;.;D;D

REVEL

Pathogenic

0.78

Sift

Benign

0.088

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

Sift4G

Uncertain

0.041

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

Polyphen

1.0

.;.;.;.;.;.;.;.;D;.

Vest4

0.93

MutPred

0.50

.;.;.;.;.;.;Loss of methylation at R942 (P = 0.0491);Loss of methylation at R942 (P = 0.0491);Loss of methylation at R942 (P = 0.0491);.;

MVP

0.86

MPC

1.4

ClinPred

1.0

GERP RS

4.5

Varity_R

0.30

gMVP

0.97

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