9-135786170-CGCCCTGCCCT-CGCCCT

Position:

• chr9-135786170-CGCCCTGCCCT-CGCCCT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020822.3(KCNT1):​c.3178-7_3178-3delTGCCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,544,516 control chromosomes in the GnomAD database, including 46,499 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7356 hom., cov: 0)
  • Exomes 𝑓: 0.24 (39143 hom.)
• Consequence: KCNT1 NM_020822.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.02

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 9-135786170-CGCCCT-C is Benign according to our data. Variant chr9-135786170-CGCCCT-C is described in ClinVar as [Benign]. Clinvar id is 196184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135786170-CGCCCT-C is described in Lovd as [Benign]. Variant chr9-135786170-CGCCCT-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3	c.3178-7_3178-3delTGCCC		splice_region_variant, intron_variant		ENST00000371757.7	NP_065873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7	c.3178-7_3178-3delTGCCC		splice_region_variant, intron_variant		1	NM_020822.3	ENSP00000360822.2

Frequencies

GnomAD3 genomes AF: 0.297 AC: 44648 AN: 150376 Hom.: 7328 Cov.: 0

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.285

GnomAD3 exomes AF: 0.242 AC: 47644 AN: 197052 Hom.: 6021 AF XY: 0.244 AC XY: 26685 AN XY: 109482

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.257

Gnomad SAS exome AF: 0.272

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.245

GnomAD4 exome AF: 0.243 AC: 338211 AN: 1394026 Hom.: 39143 AF XY: 0.244 AC XY: 169621 AN XY: 694772

Gnomad4 AFR exome AF: 0.433

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.196

Gnomad4 EAS exome AF: 0.239

Gnomad4 SAS exome AF: 0.273

Gnomad4 FIN exome AF: 0.159

Gnomad4 NFE exome AF: 0.241

Gnomad4 OTH exome AF: 0.249

GnomAD4 genome AF: 0.297 AC: 44722 AN: 150490 Hom.: 7356 Cov.: 0 AF XY: 0.290 AC XY: 21328 AN XY: 73492

Gnomad4 AFR AF: 0.451

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.206

Gnomad4 EAS AF: 0.254

Gnomad4 SAS AF: 0.259

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.282

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 31, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 42% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 39. Only high quality variants are reported. -

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

Jan 15, 2024

- -

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

clinical testing

GeneDx

Jan 04, 2016

- -

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs757968008; hg19: chr9-138678016;