chr9-135714582-C-T

Position:

chr9-135714582-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020822.3(KCNT1):c.116C>T(p.Pro39Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00551 in 1,355,446 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 34 hom. )

Consequence

KCNT1
NM_020822.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.169

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033433735).

BP6

Variant 9-135714582-C-T is Benign according to our data. Variant chr9-135714582-C-T is described in ClinVar as [Benign]. Clinvar id is 129351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135714582-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00389 (581/149260) while in subpopulation NFE AF= 0.00618 (414/66988). AF 95% confidence interval is 0.00569. There are 0 homozygotes in gnomad4. There are 272 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 581 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KCNT1	NM_020822.3 linkuse as main transcript	c.116C>T	p.Pro39Leu	missense_variant	2/31	ENST00000371757.7
KCNT1	XM_011518878.4 linkuse as main transcript	c.251C>T	p.Pro84Leu	missense_variant	2/31
KCNT1	XM_011518879.4 linkuse as main transcript	c.251C>T	p.Pro84Leu	missense_variant	2/31
KCNT1	NM_001272003.2 linkuse as main transcript	c.110+12214C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7 linkuse as main transcript	c.116C>T	p.Pro39Leu	missense_variant	2/31	1	NM_020822.3	A2	Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.00389

AC:

580

AN:

149156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00105

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.00200

Gnomad ASJ

AF:

0.00613

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00309

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00616

Gnomad OTH

AF:

0.00587

GnomAD3 exomes

AF:

0.00413

AC:

582

AN:

140822

Hom.:

AF XY:

0.00434

AC XY:

352

AN XY:

81098

show subpopulations

Gnomad AFR exome

AF:

0.000662

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.00605

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00110

Gnomad FIN exome

AF:

0.00397

Gnomad NFE exome

AF:

0.00660

Gnomad OTH exome

AF:

0.00345

GnomAD4 exome

AF:

0.00571

AC:

6886

AN:

1206186

Hom.:

Cov.:

AF XY:

0.00573

AC XY:

3421

AN XY:

597264

show subpopulations

Gnomad4 AFR exome

AF:

0.000870

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.00833

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00125

Gnomad4 FIN exome

AF:

0.00435

Gnomad4 NFE exome

AF:

0.00640

Gnomad4 OTH exome

AF:

0.00538

GnomAD4 genome

AF:

0.00389

AC:

581

AN:

149260

Hom.:

Cov.:

AF XY:

0.00373

AC XY:

272

AN XY:

72848

show subpopulations

Gnomad4 AFR

AF:

0.00104

Gnomad4 AMR

AF:

0.00200

Gnomad4 ASJ

AF:

0.00613

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00248

Gnomad4 FIN

AF:

0.00309

Gnomad4 NFE

AF:

0.00618

Gnomad4 OTH

AF:

0.00580

Alfa

AF:

0.00625

Hom.:

Bravo

AF:

0.00396

ESP6500AA

AF:

0.00123

AC:

ESP6500EA

AF:

0.00504

AC:

ExAC

AF:

0.00366

AC:

425

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2014	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

KCNT1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Developmental and epileptic encephalopathy, 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

KCNT1: BS1, BS2 -

Autosomal dominant nocturnal frontal lobe epilepsy 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.96

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.58

T;T

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.3

.;N

REVEL

Benign

0.029

Sift

Benign

0.087

.;T

Sift4G

Uncertain

0.012

D;D

Vest4

0.15

MVP

0.067

MPC

0.64

ClinPred

0.0061

GERP RS

-0.47

gMVP

0.16

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