9-135779429-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_020822.3(KCNT1):c.2800G>A(p.Ala934Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,282 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A934S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

KCNT1
NM_020822.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.53

Publications

43 publications found

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 Gene-Disease associations (from GenCC):

childhood-onset epilepsy syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 14
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
malignant migrating partial seizures of infancy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
autosomal dominant nocturnal frontal lobe epilepsy 5
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant nocturnal frontal lobe epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KCNT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_020822.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-135779429-G-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1525584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.753

PP5

Variant 9-135779429-G-A is Pathogenic according to our data. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135779429-G-A is described in CliVar as Pathogenic. Clinvar id is 39594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNT1	NM_020822.3 link	c.2800G>A	p.Ala934Thr	missense_variant	Exon 24 of 31	ENST00000371757.7	NP_065873.2	Q5JUK3-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7 link	c.2800G>A	p.Ala934Thr	missense_variant	Exon 24 of 31	1	NM_020822.3	ENSP00000360822.2		Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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

AF:

0.00000657

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74444

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41554

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Sep 26, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KCNT1: PS2, PM1, PM2, PS4:Moderate, PS3:Supporting -

Apr 07, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect as the p.A934T variant causes a marked increase in KCNT1 protein function; the mutant channel activates significantly more quickly than wild-type channels with greater current amplitude (Barcia et al., 2012; Milligan et al., 2014; Kim et al., 2014); Not observed 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: 23599387, 26122718, 23086397, 25482562, 27620904, 26785903, 26441003, 26140313, 26740507, 27779742, 27064559, 29390993, 30182498, 31054490, 31487502, 30847371, 30782581, 31872048, 31532509, 32139178, 24591078, 29100083, 32167590) -

Developmental and epileptic encephalopathy, 14

Pathogenic:3

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 07, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 934 of the KCNT1 protein (p.Ala934Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset epileptic encephalopathy, including malignant migrating partial seizures of infancy (PMID: 23086397, 25482562, 26122718, 26140313, 26993267). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 39594). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 23086397, 24591078). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

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

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

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

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.75

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

MetaSVM

Uncertain

-0.075

MutationAssessor

Benign

1.6

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

PhyloP100

9.5

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.5

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

REVEL

Pathogenic

0.67

Sift

Benign

0.067

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

Sift4G

Benign

0.075

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

Polyphen

1.0

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

Vest4

0.96

MutPred

0.46

.;.;.;.;.;.;Gain of phosphorylation at A915 (P = 0.0349);Gain of phosphorylation at A915 (P = 0.0349);Gain of phosphorylation at A915 (P = 0.0349);.;

MVP

0.79

MPC

0.81

ClinPred

0.98

GERP RS

3.8

Varity_R

0.34

gMVP

0.92

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over