rs148162797

Positions:

Variant summary

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

The NM_020822.3(KCNT1):c.2220C>G(p.Asp740Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,518,882 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D740D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 10 hom. )

Consequence

KCNT1
NM_020822.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -4.50

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=0.0068859756).

BP6

Variant 9-135772926-C-G is Benign according to our data. Variant chr9-135772926-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 473370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135772926-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000302 (46/152300) while in subpopulation SAS AF= 0.00456 (22/4822). AF 95% confidence interval is 0.00309. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3 linkuse as main transcript	c.2220C>G	p.Asp740Glu	missense_variant	19/31	ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7 linkuse as main transcript	c.2220C>G	p.Asp740Glu	missense_variant	19/31	1	NM_020822.3	A2	Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000737

AC:

AN:

126108

Hom.:

AF XY:

0.000901

AC XY:

AN XY:

67692

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000417

Gnomad ASJ exome

AF:

0.000344

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00396

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000252

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000334

AC:

456

AN:

1366582

Hom.:

Cov.:

AF XY:

0.000451

AC XY:

303

AN XY:

672564

show subpopulations

Gnomad4 AFR exome

AF:

0.0000324

Gnomad4 AMR exome

AF:

0.000326

Gnomad4 ASJ exome

AF:

0.000305

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00415

Gnomad4 FIN exome

AF:

0.000209

Gnomad4 NFE exome

AF:

0.0000768

Gnomad4 OTH exome

AF:

0.000477

GnomAD4 genome

AF:

0.000302

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00456

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000254

Hom.:

Bravo

AF:

0.000204

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000530

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	KCNT1: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2019	This variant is associated with the following publications: (PMID: 31780880) -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2018

This alteration is classified as likely 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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2020

This variant is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Autosomal dominant nocturnal frontal lobe epilepsy 5

Benign:1

Likely 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

0.079

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.0020

DANN

Benign

0.47

DEOGEN2

Benign

0.043

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

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.72

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

M_CAP

Benign

0.023

MetaRNN

Benign

0.0069

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

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

MutationTaster

Benign

0.91

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

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.88

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

REVEL

Benign

0.22

Sift

Benign

0.72

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

Sift4G

Benign

0.50

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

Polyphen

0.0030

.;.;.;.;.;.;.;.;B;.

Vest4

0.27

MutPred

0.41

.;.;.;.;.;.;Gain of solvent accessibility (P = 0.0155);Gain of solvent accessibility (P = 0.0155);Gain of solvent accessibility (P = 0.0155);.;

MVP

0.66

MPC

0.59

ClinPred

0.012

GERP RS

-7.8

Varity_R

0.033

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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