rs886043455

Variant names:

• chr9-135784031-G-A
• rs886043455
• NM_020822.3:c.2849G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-135784031-G-A
• chr9-135784031-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 9.68

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]

ACMG classification

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 rank	MANE	Protein	UniProt
KCNT1	NM_020822.3	c.2849G>A	p.Arg950Gln	missense_variant	Exon 25 of 31	ENST00000371757.7	NP_065873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7	c.2849G>A	p.Arg950Gln	missense_variant	Exon 25 of 31	1	NM_020822.3	ENSP00000360822.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454204 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 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.: 33

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 14 Pathogenic:3

Feb 15, 2017

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 27, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2 Uncertain:1

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 26, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 17, 2021

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	.;.;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.054	T
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;.;.;M;.
PrimateAI	Uncertain	0.73	T
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	D
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

Other links and lift over

dbSNP: rs886043455; hg19: chr9-138675877;