9-135714602-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_020822.3(KCNT1):c.136C>T(p.Leu46Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000265 in 1,281,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

KCNT1
NM_020822.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.17

Publications

1 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

childhood-onset epilepsy syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 14
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
malignant migrating partial seizures of infancy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
autosomal dominant nocturnal frontal lobe epilepsy 5
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant nocturnal frontal lobe epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KCNT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09466401).

BP6

Variant 9-135714602-C-T is Benign according to our data. Variant chr9-135714602-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 224110.

BS2

High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KCNT1	NM_020822.3 link	c.136C>T	p.Leu46Phe	missense_variant	Exon 2 of 31	ENST00000371757.7	NP_065873.2
KCNT1	XM_011518878.4 link	c.271C>T	p.Leu91Phe	missense_variant	Exon 2 of 31		XP_011517180.1
KCNT1	XM_011518879.4 link	c.271C>T	p.Leu91Phe	missense_variant	Exon 2 of 31		XP_011517181.1
KCNT1	NM_001272003.2 link	c.110+12234C>T		intron_variant	Intron 1 of 30		NP_001258932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7 link	c.136C>T	p.Leu46Phe	missense_variant	Exon 2 of 31	1	NM_020822.3	ENSP00000360822.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000265

AC:

AN:

1281190

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

637266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25590

American (AMR)

AF:

0.00

AC:

AN:

32504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20020

East Asian (EAS)

AF:

0.0000396

AC:

AN:

25232

South Asian (SAS)

AF:

0.00

AC:

AN:

73450

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3982

European-Non Finnish (NFE)

AF:

0.0000307

AC:

AN:

1011272

Other (OTH)

AF:

0.0000407

AC:

AN:

49132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000379

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

May 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 46 of the KCNT1 protein (p.Leu46Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability, autism spectrum disorder, speech delay, and seizures (PMID: 28554332). ClinVar contains an entry for this variant (Variation ID: 224110). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNT1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Developmental and epileptic encephalopathy, 14

Benign:1

Apr 16, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.39

T;T

M_CAP

Benign

0.076

MetaRNN

Benign

0.095

T;T

MetaSVM

Benign

-0.98

PhyloP100

2.2

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.30

.;N

REVEL

Benign

0.053

Sift

Benign

0.22

.;T

Sift4G

Uncertain

0.044

D;D

Vest4

0.097

MutPred

0.18

Gain of catalytic residue at L46 (P = 0.0236);Gain of catalytic residue at L46 (P = 0.0236);

MVP

0.081

MPC

0.69

ClinPred

0.66

GERP RS

2.7

PromoterAI

0.080

Neutral

(source)

gMVP

0.17

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over