rs138421850

Positions:

Variant summary

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

The ENST00000371757.7(KCNT1):c.3388G>A(p.Ala1130Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,576,966 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1130S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0098 ( 15 hom., cov: 33)

Exomes 𝑓: 0.013 ( 144 hom. )

Consequence

KCNT1
ENST00000371757.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.13

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=0.004505396).

BP6

Variant 9-135786407-G-A is Benign according to our data. Variant chr9-135786407-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135786407-G-A is described in Lovd as [Benign]. Variant chr9-135786407-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00978 (1489/152318) while in subpopulation AMR AF= 0.0142 (217/15312). AF 95% confidence interval is 0.0126. There are 15 homozygotes in gnomad4. There are 747 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1489 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3 linkuse as main transcript	c.3388G>A	p.Ala1130Thr	missense_variant	29/31	ENST00000371757.7	NP_065873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7 linkuse as main transcript	c.3388G>A	p.Ala1130Thr	missense_variant	29/31	1	NM_020822.3	ENSP00000360822	A2	Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.00980

AC:

1491

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0142

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00911

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.0133

Gnomad OTH

AF:

0.0191

GnomAD3 exomes

AF:

0.0104

AC:

1844

AN:

176890

Hom.:

AF XY:

0.0106

AC XY:

1035

AN XY:

97708

show subpopulations

Gnomad AFR exome

AF:

0.00315

Gnomad AMR exome

AF:

0.00814

Gnomad ASJ exome

AF:

0.00845

Gnomad EAS exome

AF:

0.0000745

Gnomad SAS exome

AF:

0.00885

Gnomad FIN exome

AF:

0.0148

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.0126

AC:

17924

AN:

1424648

Hom.:

144

Cov.:

AF XY:

0.0125

AC XY:

8818

AN XY:

705736

show subpopulations

Gnomad4 AFR exome

AF:

0.00199

Gnomad4 AMR exome

AF:

0.00988

Gnomad4 ASJ exome

AF:

0.00772

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00887

Gnomad4 FIN exome

AF:

0.0136

Gnomad4 NFE exome

AF:

0.0137

Gnomad4 OTH exome

AF:

0.0131

GnomAD4 genome

AF:

0.00978

AC:

1489

AN:

152318

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

747

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00284

Gnomad4 AMR

AF:

0.0142

Gnomad4 ASJ

AF:

0.00662

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00911

Gnomad4 FIN

AF:

0.0121

Gnomad4 NFE

AF:

0.0133

Gnomad4 OTH

AF:

0.0184

Alfa

AF:

0.00787

Hom.:

Bravo

AF:

0.00951

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00246

AC:

ESP6500EA

AF:

0.0106

AC:

ExAC

AF:

0.00790

AC:

909

Asia WGS

AF:

0.00491

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2014	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KCNT1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 15, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Autosomal dominant nocturnal frontal lobe epilepsy 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jul 05, 2019	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

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

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 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. -

Developmental and epileptic encephalopathy, 14

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

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.65

CADD

Benign

5.0

DANN

Benign

0.90

DEOGEN2

Benign

0.030

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

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.74

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

MetaRNN

Benign

0.0045

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

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

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

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.67

N;.;N;.;.;.;.;.;.;N

REVEL

Benign

0.028

Sift

Uncertain

0.012

D;.;T;.;.;.;.;.;.;T

Sift4G

Benign

0.45

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

Vest4

0.25

MPC

0.092

ClinPred

0.0033

GERP RS

-1.1

Varity_R

0.028

gMVP

0.37

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