rs914428

Positions:

chr9-135777415-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_020822.3(KCNT1):c.2427G>A(p.Thr809=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.676 in 1,613,708 control chromosomes in the GnomAD database, including 372,007 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 32274 hom., cov: 33)

Exomes 𝑓: 0.68 ( 339733 hom. )

Consequence

KCNT1
NM_020822.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -3.94

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 9-135777415-G-A is Benign according to our data. Variant chr9-135777415-G-A is described in ClinVar as [Benign]. Clinvar id is 129357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135777415-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.94 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3 linkuse as main transcript	c.2427G>A	p.Thr809=	synonymous_variant	21/31	ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7 linkuse as main transcript	c.2427G>A	p.Thr809=	synonymous_variant	21/31	1	NM_020822.3	A2	Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.647

AC:

98304

AN:

151916

Hom.:

32246

Cov.:

show subpopulations

Gnomad AFR

AF:

0.567

Gnomad AMI

AF:

0.796

Gnomad AMR

AF:

0.663

Gnomad ASJ

AF:

0.488

Gnomad EAS

AF:

0.588

Gnomad SAS

AF:

0.751

Gnomad FIN

AF:

0.766

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.679

Gnomad OTH

AF:

0.613

GnomAD3 exomes

AF:

0.668

AC:

167817

AN:

251278

Hom.:

56838

AF XY:

0.671

AC XY:

91156

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.557

Gnomad AMR exome

AF:

0.659

Gnomad ASJ exome

AF:

0.496

Gnomad EAS exome

AF:

0.592

Gnomad SAS exome

AF:

0.748

Gnomad FIN exome

AF:

0.764

Gnomad NFE exome

AF:

0.675

Gnomad OTH exome

AF:

0.645

GnomAD4 exome

AF:

0.679

AC:

993200

AN:

1461674

Hom.:

339733

Cov.:

AF XY:

0.681

AC XY:

495342

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.562

Gnomad4 AMR exome

AF:

0.658

Gnomad4 ASJ exome

AF:

0.491

Gnomad4 EAS exome

AF:

0.576

Gnomad4 SAS exome

AF:

0.738

Gnomad4 FIN exome

AF:

0.766

Gnomad4 NFE exome

AF:

0.686

Gnomad4 OTH exome

AF:

0.652

GnomAD4 genome

AF:

0.647

AC:

98378

AN:

152034

Hom.:

32274

Cov.:

AF XY:

0.651

AC XY:

48364

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.567

Gnomad4 AMR

AF:

0.663

Gnomad4 ASJ

AF:

0.488

Gnomad4 EAS

AF:

0.588

Gnomad4 SAS

AF:

0.751

Gnomad4 FIN

AF:

0.766

Gnomad4 NFE

AF:

0.679

Gnomad4 OTH

AF:

0.616

Alfa

AF:

0.658

Hom.:

55834

Bravo

AF:

0.630

Asia WGS

AF:

0.667

AC:

2320

AN:

3478

EpiCase

AF:

0.659

EpiControl

AF:

0.642

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 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	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 88% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 82. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 06, 2018	- -

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

Dec 31, 2015

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

Aug 19, 2021

- -

Autosomal dominant nocturnal frontal lobe epilepsy 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

1.0

DANN

Benign

0.84

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