9-135770463-A-G

Position:

• chr9-135770463-A-G

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.1769+16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 1,600,964 control chromosomes in the GnomAD database, including 407,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39790 hom., cov: 36)
  • Exomes 𝑓: 0.71 (367946 hom.)
• Consequence: KCNT1 NM_020822.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.457

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=-0.88).
• BP6: Variant 9-135770463-A-G is Benign according to our data. Variant chr9-135770463-A-G is described in ClinVar as [Benign]. Clinvar id is 194782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135770463-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.1769+16A>G		intron_variant		ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.1769+16A>G		intron_variant		1	NM_020822.3	A2

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109650 AN: 152070 Hom.: 39746 Cov.: 36

Gnomad AFR AF: 0.771

Gnomad AMI AF: 0.663

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.712

Gnomad SAS AF: 0.795

Gnomad FIN AF: 0.746

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.675

GnomAD3 exomes AF: 0.707 AC: 168006 AN: 237642 Hom.: 59700 AF XY: 0.710 AC XY: 91025 AN XY: 128254

Gnomad AFR exome AF: 0.776

Gnomad AMR exome AF: 0.638

Gnomad ASJ exome AF: 0.587

Gnomad EAS exome AF: 0.707

Gnomad SAS exome AF: 0.787

Gnomad FIN exome AF: 0.744

Gnomad NFE exome AF: 0.701

Gnomad OTH exome AF: 0.687

GnomAD4 exome AF: 0.712 AC: 1031260 AN: 1448772 Hom.: 367946 Cov.: 49 AF XY: 0.714 AC XY: 513611 AN XY: 719634

Gnomad4 AFR exome AF: 0.778

Gnomad4 AMR exome AF: 0.638

Gnomad4 ASJ exome AF: 0.593

Gnomad4 EAS exome AF: 0.704

Gnomad4 SAS exome AF: 0.783

Gnomad4 FIN exome AF: 0.745

Gnomad4 NFE exome AF: 0.710

Gnomad4 OTH exome AF: 0.696

GnomAD4 genome AF: 0.721 AC: 109750 AN: 152192 Hom.: 39790 Cov.: 36 AF XY: 0.722 AC XY: 53687 AN XY: 74398

Gnomad4 AFR AF: 0.771

Gnomad4 AMR AF: 0.658

Gnomad4 ASJ AF: 0.590

Gnomad4 EAS AF: 0.712

Gnomad4 SAS AF: 0.795

Gnomad4 FIN AF: 0.746

Gnomad4 NFE AF: 0.705

Gnomad4 OTH AF: 0.678

Alfa AF: 0.695 Hom.: 45113

Bravo AF: 0.710

Asia WGS AF: 0.771 AC: 2684 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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 86% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 80. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Aug 19, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Autosomal dominant nocturnal frontal lobe epilepsy 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.29

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: rs10776844; hg19: chr9-138662309; COSMIC: COSV53701950; COSMIC: COSV53701950;