9-135786170-CGCCCTGCCCT-CGCCCTGCCCTGCCCTGCCCT

Position:

• chr9-135786170-CGCCCTGCCCT-CGCCCTGCCCTGCCCTGCCCT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The NM_020822.3(KCNT1):​c.3178-12_3178-3dupTGCCCTGCCC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: KCNT1 NM_020822.3 splice_acceptor, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.600

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 -8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• BP6: Variant 9-135786170-C-CGCCCTGCCCT is Benign according to our data. Variant chr9-135786170-C-CGCCCTGCCCT is described in ClinVar as [Likely_benign]. Clinvar id is 421819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000518 (78/150642) while in subpopulation EAS AF= 0.00118 (6/5068). AF 95% confidence interval is 0.00053. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 78 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3	c.3178-12_3178-3dupTGCCCTGCCC		splice_acceptor_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.3178-12_3178-3dupTGCCCTGCCC		splice_acceptor_variant, intron_variant		1	NM_020822.3	ENSP00000360822.2

Frequencies

GnomAD3 genomes AF: 0.000525 AC: 79 AN: 150528 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000738

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000395

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00118

Gnomad SAS AF: 0.000842

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000414

Gnomad OTH AF: 0.000969

GnomAD3 exomes AF: 0.000401 AC: 79 AN: 197052 Hom.: 0 AF XY: 0.000420 AC XY: 46 AN XY: 109482

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00104

Gnomad SAS exome AF: 0.000616

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000331 AC: 462 AN: 1397630 Hom.: 2 Cov.: 12 AF XY: 0.000356 AC XY: 248 AN XY: 696464

Gnomad4 AFR exome AF: 0.000327

Gnomad4 AMR exome AF: 0.000360

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.000932

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.0000198

Gnomad4 NFE exome AF: 0.000315

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000518 AC: 78 AN: 150642 Hom.: 0 Cov.: 0 AF XY: 0.000462 AC XY: 34 AN XY: 73586

Gnomad4 AFR AF: 0.000736

Gnomad4 AMR AF: 0.000394

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00118

Gnomad4 SAS AF: 0.000843

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000399

Gnomad4 OTH AF: 0.000959

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 01, 2018	- -

KCNT1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 28, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Developmental and epileptic encephalopathy, 14 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Autosomal dominant nocturnal frontal lobe epilepsy 5 Benign:1

Likely 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;