9-135786407-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_020822.3(KCNT1):c.3388G>T(p.Ala1130Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000381 in 1,576,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1130T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

KCNT1
NM_020822.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13

Publications

10 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08468565).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNT1	NM_020822.3 link	c.3388G>T	p.Ala1130Ser	missense_variant	Exon 29 of 31	ENST00000371757.7	NP_065873.2	Q5JUK3-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7 link	c.3388G>T	p.Ala1130Ser	missense_variant	Exon 29 of 31	1	NM_020822.3	ENSP00000360822.2		Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000113

AC:

AN:

176890

AF XY:

0.0000205

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000142

Gnomad OTH exome

AF:

0.000210

GnomAD4 exome

AF:

0.00000351

AC:

AN:

1424656

Hom.:

Cov.:

AF XY:

0.00000567

AC XY:

AN XY:

705744

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32602

American (AMR)

AF:

0.00

AC:

AN:

39768

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25512

East Asian (EAS)

AF:

0.0000531

AC:

AN:

37690

South Asian (SAS)

AF:

0.00

AC:

AN:

82522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48808

Middle Eastern (MID)

AF:

0.000209

AC:

AN:

4780

European-Non Finnish (NFE)

AF:

9.14e-7

AC:

AN:

1094116

Other (OTH)

AF:

0.0000170

AC:

AN:

58858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00000861

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Aug 15, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. 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. This variant has not been reported in the literature in individuals with KCNT1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces alanine with serine at codon 1130 of the KCNT1 protein (p.Ala1130Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

5.5

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.028

.;.;.;.;.;.;.;.;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.83

T;T;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.085

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

.;.;.;.;.;.;.;.;L;.

PhyloP100

1.1

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.46

N;.;N;.;.;.;.;.;.;N

REVEL

Benign

0.013

Sift

Benign

0.034

D;.;T;.;.;.;.;.;.;T

Sift4G

Benign

0.33

T;T;T;T;T;T;T;T;T;T

Vest4

0.29

MVP

0.27

MPC

0.095

ClinPred

0.050

GERP RS

-1.1

Varity_R

0.042

gMVP

0.30

Mutation Taster

=94/6

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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