rs886043455

Positions:

Variant summary

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

The NM_020822.3(KCNT1):c.2849G>A(p.Arg950Gln) 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: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNT1
NM_020822.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:1

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:

KCNT1 (HGNC:):

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, 0.833

PP5

Variant 9-135784031-G-A is Pathogenic according to our data. Variant chr9-135784031-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 286710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135784031-G-A is described in Lovd as [Pathogenic]. Variant chr9-135784031-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 linkuse as main transcript	c.2849G>A	p.Arg950Gln	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 linkuse as main transcript	c.2849G>A	p.Arg950Gln	missense_variant	25/31	1	NM_020822.3	ENSP00000360822.2		Q5JUK3-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1454204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723792

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:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 14

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Feb 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000286710). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 26122718 , 27029629 , 29100083). A different missense change at the same codon (p.Arg950Leu) has been reported to be associated with KCNT1-related disorder (ClinVar ID: VCV000473378). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:2Uncertain:1

Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Mar 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2022	Published functional studies demonstrate a gain-of-function phenotype (Dilena et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29694806, 29056246, 26122718, 27029629, 29196578, 28488083, 29100083, 31487502, 30847371, 32167590, 30112700) -

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

Dec 07, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 950 of the KCNT1 protein (p.Arg950Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with infantile seizures, epilepsy and developmental delay (PMID: 26122718, 27029629, 29100083). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 286710). 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%. This variant disrupts the p.Arg950 amino acid residue in KCNT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2023

The c.2849G>A (p.R950Q) alteration is located in exon 25 (coding exon 25) of the KCNT1 gene. This alteration results from a G to A substitution at nucleotide position 2849, causing the arginine (R) at amino acid position 950 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in the heterozygous state in multiple individuals with clinical features of KCNT1-related neurodevelopmental disorder and has been determined to be the result of a de novo mutation multiple individuals (Bonardi, 2021; Borlot, 2020; Costain, 2019; Dilena, 2018; Hamdan, 2017; Hildebrand, 2016; Møller, 2015). In addition, this alteration was reported to cosegregate with disease in one family (Rubboli, 2019). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies indicate this alteration leads to a shift in the half-activation voltage and support a gain-of-function impact on channel properties (Hinckley, 2023; Dilena, 2018). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Seizure

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

May 17, 2021

missense variant absnet from gnomad. Previously described in the litterature. de novo -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

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

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.83

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

MetaSVM

Uncertain

-0.054

MutationAssessor

Uncertain

2.5

.;.;.;.;.;.;.;.;M;.

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.0

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

REVEL

Uncertain

0.52

Sift

Uncertain

0.012

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

Sift4G

Uncertain

0.0070

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

Polyphen

0.97

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

Vest4

0.96

MutPred

0.23

.;.;.;.;.;.;Loss of MoRF binding (P = 0.1822);Loss of MoRF binding (P = 0.1822);Loss of MoRF binding (P = 0.1822);.;

MVP

0.88

MPC

1.0

ClinPred

0.99

GERP RS

4.5

Varity_R

0.32

gMVP

0.91

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