chr9-135770427-G-A

Position:

chr9-135770427-G-A

Variant summary

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

The ENST00000371757.7(KCNT1):c.1749G>A(p.Ala583=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,612,168 control chromosomes in the GnomAD database, including 50,457 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. A583A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.30 ( 7877 hom., cov: 34)

Exomes 𝑓: 0.23 ( 42580 hom. )

Consequence

KCNT1
ENST00000371757.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.68

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=-0.51).

BP6

Variant 9-135770427-G-A is Benign according to our data. Variant chr9-135770427-G-A is described in ClinVar as [Benign]. Clinvar id is 129353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135770427-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.68 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3 linkuse as main transcript	c.1749G>A	p.Ala583=	synonymous_variant	17/31	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.1749G>A	p.Ala583=	synonymous_variant	17/31	1	NM_020822.3	ENSP00000360822	A2	Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.299

AC:

45412

AN:

152056

Hom.:

7858

Cov.:

show subpopulations

Gnomad AFR

AF:

0.468

Gnomad AMI

AF:

0.127

Gnomad AMR

AF:

0.207

Gnomad ASJ

AF:

0.156

Gnomad EAS

AF:

0.417

Gnomad SAS

AF:

0.354

Gnomad FIN

AF:

0.316

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.212

Gnomad OTH

AF:

0.250

GnomAD3 exomes

AF:

0.259

AC:

64505

AN:

249284

Hom.:

9531

AF XY:

0.256

AC XY:

34612

AN XY:

134950

show subpopulations

Gnomad AFR exome

AF:

0.481

Gnomad AMR exome

AF:

0.177

Gnomad ASJ exome

AF:

0.152

Gnomad EAS exome

AF:

0.420

Gnomad SAS exome

AF:

0.321

Gnomad FIN exome

AF:

0.324

Gnomad NFE exome

AF:

0.208

Gnomad OTH exome

AF:

0.226

GnomAD4 exome

AF:

0.231

AC:

337040

AN:

1459994

Hom.:

42580

Cov.:

AF XY:

0.232

AC XY:

168726

AN XY:

726302

show subpopulations

Gnomad4 AFR exome

AF:

0.479

Gnomad4 AMR exome

AF:

0.181

Gnomad4 ASJ exome

AF:

0.157

Gnomad4 EAS exome

AF:

0.437

Gnomad4 SAS exome

AF:

0.317

Gnomad4 FIN exome

AF:

0.317

Gnomad4 NFE exome

AF:

0.209

Gnomad4 OTH exome

AF:

0.236

GnomAD4 genome

AF:

0.299

AC:

45470

AN:

152174

Hom.:

7877

Cov.:

AF XY:

0.303

AC XY:

22572

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.468

Gnomad4 AMR

AF:

0.207

Gnomad4 ASJ

AF:

0.156

Gnomad4 EAS

AF:

0.417

Gnomad4 SAS

AF:

0.354

Gnomad4 FIN

AF:

0.316

Gnomad4 NFE

AF:

0.212

Gnomad4 OTH

AF:

0.254

Alfa

AF:

0.248

Hom.:

3281

Bravo

AF:

0.297

Asia WGS

AF:

0.388

AC:

1349

AN:

3478

EpiCase

AF:

0.195

EpiControl

AF:

0.189

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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, 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 29% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 27. Only high quality variants are reported. -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2014	- -
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	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Jan 08, 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

- -

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_noAF

Benign

-0.51

CADD

Benign

9.5

DANN

Benign

0.93

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