rs112341167

Positions:

• chr9-135765016-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020822.3(KCNT1):​c.1036-15G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,599,926 control chromosomes in the GnomAD database, including 445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (66 hom., cov: 32)
  • Exomes 𝑓: 0.019 (379 hom.)
• Consequence: KCNT1 NM_020822.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.27

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=-0.86).
• BP6: Variant 9-135765016-G-A is Benign according to our data. Variant chr9-135765016-G-A is described in ClinVar as [Benign]. Clinvar id is 261360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135765016-G-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3	c.1036-15G>A		splice_polypyrimidine_tract_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.1036-15G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_020822.3	ENSP00000360822	A2

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3807 AN: 152170 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.0366

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.0553

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00785

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0209

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0189 AC: 4661 AN: 246050 Hom.: 76 AF XY: 0.0187 AC XY: 2499 AN XY: 133520

Gnomad AFR exome AF: 0.0382

Gnomad AMR exome AF: 0.0192

Gnomad ASJ exome AF: 0.0465

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00793

Gnomad FIN exome AF: 0.00336

Gnomad NFE exome AF: 0.0222

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0195 AC: 28170 AN: 1447638 Hom.: 379 Cov.: 33 AF XY: 0.0193 AC XY: 13842 AN XY: 717150

Gnomad4 AFR exome AF: 0.0376

Gnomad4 AMR exome AF: 0.0205

Gnomad4 ASJ exome AF: 0.0495

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.00854

Gnomad4 FIN exome AF: 0.00348

Gnomad4 NFE exome AF: 0.0199

Gnomad4 OTH exome AF: 0.0253

GnomAD4 genome AF: 0.0250 AC: 3807 AN: 152288 Hom.: 66 Cov.: 32 AF XY: 0.0241 AC XY: 1798 AN XY: 74464

Gnomad4 AFR AF: 0.0366

Gnomad4 AMR AF: 0.0334

Gnomad4 ASJ AF: 0.0553

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00765

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.0209

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0248 Hom.: 20

Bravo AF: 0.0279

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.86
CADD	Benign	0.17
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs112341167; hg19: chr9-138656862;