rs201051863

Positions:

• chr9-135714582-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020822.3(KCNT1):​c.116C>T​(p.Pro39Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00551 in 1,355,446 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (34 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.169

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 (MetaRNN=0.0033433735).
• BP6: Variant 9-135714582-C-T is Benign according to our data. Variant chr9-135714582-C-T is described in ClinVar as [Benign]. Clinvar id is 129351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135714582-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00389 (581/149260) while in subpopulation NFE AF= 0.00618 (414/66988). AF 95% confidence interval is 0.00569. There are 0 homozygotes in gnomad4. There are 272 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 581 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.116C>T	p.Pro39Leu	missense_variant	2/31	ENST00000371757.7
KCNT1	XM_011518878.4	c.251C>T	p.Pro84Leu	missense_variant	2/31
KCNT1	XM_011518879.4	c.251C>T	p.Pro84Leu	missense_variant	2/31
KCNT1	NM_001272003.2	c.110+12214C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.116C>T	p.Pro39Leu	missense_variant	2/31	1	NM_020822.3	A2

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 580 AN: 149156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00105

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00200

Gnomad ASJ AF: 0.00613

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00309

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00616

Gnomad OTH AF: 0.00587

GnomAD3 exomes AF: 0.00413 AC: 582 AN: 140822 Hom.: 6 AF XY: 0.00434 AC XY: 352 AN XY: 81098

Gnomad AFR exome AF: 0.000662

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00605

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00110

Gnomad FIN exome AF: 0.00397

Gnomad NFE exome AF: 0.00660

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00571 AC: 6886 AN: 1206186 Hom.: 34 Cov.: 30 AF XY: 0.00573 AC XY: 3421 AN XY: 597264

Gnomad4 AFR exome AF: 0.000870

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00833

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00125

Gnomad4 FIN exome AF: 0.00435

Gnomad4 NFE exome AF: 0.00640

Gnomad4 OTH exome AF: 0.00538

GnomAD4 genome AF: 0.00389 AC: 581 AN: 149260 Hom.: 0 Cov.: 32 AF XY: 0.00373 AC XY: 272 AN XY: 72848

Gnomad4 AFR AF: 0.00104

Gnomad4 AMR AF: 0.00200

Gnomad4 ASJ AF: 0.00613

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00309

Gnomad4 NFE AF: 0.00618

Gnomad4 OTH AF: 0.00580

Alfa AF: 0.00625 Hom.: 0

Bravo AF: 0.00396

ESP6500AA AF: 0.00123 AC: 5

ESP6500EA AF: 0.00504 AC: 41

ExAC AF: 0.00366 AC: 425

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 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. -

Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

KCNT1: BS1, BS2 -

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_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	15
DANN	Benign	0.96
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.58	T;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.69	T
Sift4G	Uncertain	0.012	D;D
Vest4		0.15
MVP		0.067
MPC		0.64
ClinPred		0.0061	T
GERP RS		-0.47
gMVP		0.16

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: rs201051863; hg19: chr9-138606428;