9-135786170-CGCCCTGCCCT-CGCCCTGCCCTGCCCT

Position:

• chr9-135786170-CGCCCTGCCCT-CGCCCTGCCCTGCCCT

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.3178-7_3178-3dupTGCCC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0063 (23 hom.)
• Consequence: KCNT1 NM_020822.3 splice_acceptor, intron
• Clinical Significance: 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-CGCCCT is Benign according to our data. Variant chr9-135786170-C-CGCCCT is described in ClinVar as [Benign]. Clinvar id is 196185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00574 (865/150638) while in subpopulation AMR AF= 0.00868 (132/15210). AF 95% confidence interval is 0.00747. There are 3 homozygotes in gnomad4. There are 411 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 865 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3	c.3178-7_3178-3dupTGCCC		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.3178-7_3178-3dupTGCCC		splice_acceptor_variant, intron_variant		1	NM_020822.3	ENSP00000360822.2

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 865 AN: 150524 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00869

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00413

Gnomad SAS AF: 0.00253

Gnomad FIN AF: 0.00315

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00736

Gnomad OTH AF: 0.00727

GnomAD3 exomes AF: 0.00488 AC: 962 AN: 197052 Hom.: 3 AF XY: 0.00464 AC XY: 508 AN XY: 109482

Gnomad AFR exome AF: 0.00330

Gnomad AMR exome AF: 0.00619

Gnomad ASJ exome AF: 0.00331

Gnomad EAS exome AF: 0.00414

Gnomad SAS exome AF: 0.00262

Gnomad FIN exome AF: 0.00274

Gnomad NFE exome AF: 0.00601

Gnomad OTH exome AF: 0.00593

GnomAD4 exome AF: 0.00634 AC: 8863 AN: 1397248 Hom.: 23 Cov.: 12 AF XY: 0.00629 AC XY: 4377 AN XY: 696296

Gnomad4 AFR exome AF: 0.00324

Gnomad4 AMR exome AF: 0.00708

Gnomad4 ASJ exome AF: 0.00350

Gnomad4 EAS exome AF: 0.00417

Gnomad4 SAS exome AF: 0.00314

Gnomad4 FIN exome AF: 0.00333

Gnomad4 NFE exome AF: 0.00695

Gnomad4 OTH exome AF: 0.00636

GnomAD4 genome AF: 0.00574 AC: 865 AN: 150638 Hom.: 3 Cov.: 0 AF XY: 0.00559 AC XY: 411 AN XY: 73584

Gnomad4 AFR AF: 0.00334

Gnomad4 AMR AF: 0.00868

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00414

Gnomad4 SAS AF: 0.00253

Gnomad4 FIN AF: 0.00315

Gnomad4 NFE AF: 0.00736

Gnomad4 OTH AF: 0.00719

Bravo AF: 0.00608

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 31, 2016

- -

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

Jul 19, 2021

- -

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 26, 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;