rs28612938

Positions:

chr9-135784131-C-T

Variant summary

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

The NM_020822.3(KCNT1):c.2943+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 1,601,074 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 37 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 57 hom. )

Consequence

KCNT1
NM_020822.3 splice_region, intron

Scores

Splicing: ADA: 0.00002636

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.756

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:

KCNT1 (HGNC:):

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 (BayesDel_noAF=-0.83).

BP6

Variant 9-135784131-C-T is Benign according to our data. Variant chr9-135784131-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135784131-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0135 (2063/152320) while in subpopulation AFR AF= 0.0401 (1668/41566). AF 95% confidence interval is 0.0385. There are 37 homozygotes in gnomad4. There are 973 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2063 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3 linkuse as main transcript	c.2943+6C>T		splice_region_variant, intron_variant		ENST00000371757.7	NP_065873.2	Q5JUK3-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7 linkuse as main transcript	c.2943+6C>T		splice_region_variant, intron_variant		1	NM_020822.3	ENSP00000360822.2		Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.0135

AC:

2053

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0400

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0110

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.00191

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.00559

AC:

1353

AN:

242072

Hom.:

AF XY:

0.00466

AC XY:

615

AN XY:

131920

show subpopulations

Gnomad AFR exome

AF:

0.0426

Gnomad AMR exome

AF:

0.00573

Gnomad ASJ exome

AF:

0.00917

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00229

Gnomad FIN exome

AF:

0.000144

Gnomad NFE exome

AF:

0.00229

Gnomad OTH exome

AF:

0.00743

GnomAD4 exome

AF:

0.00311

AC:

4508

AN:

1448754

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

2162

AN XY:

721216

show subpopulations

Gnomad4 AFR exome

AF:

0.0451

Gnomad4 AMR exome

AF:

0.00655

Gnomad4 ASJ exome

AF:

0.00877

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00155

Gnomad4 OTH exome

AF:

0.00615

GnomAD4 genome

AF:

0.0135

AC:

2063

AN:

152320

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

973

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0401

Gnomad4 AMR

AF:

0.0110

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00191

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0104

Hom.:

Bravo

AF:

0.0156

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.00305

EpiControl

AF:

0.00350

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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 13, 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. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 07, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 12, 2017	- -

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

- -

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

-0.83

CADD

Benign

5.2

DANN

Benign

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000026

dbscSNV1_RF

Benign

0.0040

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