rs61744696

Positions:

chr9-135772916-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The ENST00000371757.7(KCNT1):c.2210C>T(p.Thr737Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,529,262 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T737T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 22 hom., cov: 33)

Exomes 𝑓: 0.015 ( 190 hom. )

Consequence

KCNT1
ENST00000371757.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.69

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 -16 ACMG points.

BP6

Variant 9-135772916-C-T is Benign according to our data. Variant chr9-135772916-C-T is described in ClinVar as [Benign]. Clinvar id is 129356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135772916-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.012 (1826/152294) while in subpopulation NFE AF= 0.0173 (1175/68024). AF 95% confidence interval is 0.0165. There are 22 homozygotes in gnomad4. There are 886 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1826 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3 linkuse as main transcript	c.2210C>T	p.Thr737Met	missense_variant	19/31	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.2210C>T	p.Thr737Met	missense_variant	19/31	1	NM_020822.3	ENSP00000360822	A2	Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1826

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00297

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.00894

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0276

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0173

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0123

AC:

1673

AN:

136438

Hom.:

AF XY:

0.0121

AC XY:

891

AN XY:

73924

show subpopulations

Gnomad AFR exome

AF:

0.00319

Gnomad AMR exome

AF:

0.00909

Gnomad ASJ exome

AF:

0.0122

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00130

Gnomad FIN exome

AF:

0.0283

Gnomad NFE exome

AF:

0.0175

Gnomad OTH exome

AF:

0.0130

GnomAD4 exome

AF:

0.0152

AC:

20987

AN:

1376968

Hom.:

190

Cov.:

AF XY:

0.0148

AC XY:

10060

AN XY:

678806

show subpopulations

Gnomad4 AFR exome

AF:

0.00217

Gnomad4 AMR exome

AF:

0.0101

Gnomad4 ASJ exome

AF:

0.0109

Gnomad4 EAS exome

AF:

0.0000559

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.0269

Gnomad4 NFE exome

AF:

0.0170

Gnomad4 OTH exome

AF:

0.0141

GnomAD4 genome

AF:

0.0120

AC:

1826

AN:

152294

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

886

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00296

Gnomad4 AMR

AF:

0.0108

Gnomad4 ASJ

AF:

0.00894

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0276

Gnomad4 NFE

AF:

0.0173

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0141

Hom.:

Bravo

AF:

0.0112

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.00410

AC:

ESP6500EA

AF:

0.0153

AC:

131

ExAC

AF:

0.00814

AC:

959

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 30, 2015	- -
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	GeneDx	Jan 07, 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. -

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

Feb 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. -

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

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.073

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

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.87

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

MetaRNN

Benign

0.0040

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

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.9

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

MutationTaster

Benign

0.94

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

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.1

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

REVEL

Benign

0.23

Sift

Benign

0.082

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

Sift4G

Benign

0.097

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

Polyphen

0.11

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

Vest4

0.35

MPC

0.67

ClinPred

0.0068

GERP RS

3.0

Varity_R

0.061

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: -5

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