rs28612938

Positions:

• chr9-135784131-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020822.3(KCNT1):​c.2943+6C>T variant causes a splice donor 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. 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_donor_region, intron
• Scores: Splicing: ADA: 0.00002636
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.756

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]

ACMG classification

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	UniProt
KCNT1	NM_020822.3	c.2943+6C>T		splice_donor_region_variant, intron_variant		ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.2943+6C>T		splice_donor_region_variant, intron_variant		1	NM_020822.3	A2

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2053 AN: 152202 Hom.: 37 Cov.: 33

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.: 18 AF XY: 0.00466 AC XY: 615 AN XY: 131920

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.: 57 Cov.: 31 AF XY: 0.00300 AC XY: 2162 AN XY: 721216

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.: 37 Cov.: 33 AF XY: 0.0131 AC XY: 973 AN XY: 74484

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.: 8

Bravo AF: 0.0156

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00350

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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, 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:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 07, 2018	- -
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

Invitae

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

Other links and lift over

dbSNP: rs28612938; hg19: chr9-138675977;