Genetic Variant KCNT1:p.Arg1230Leu (chr9-135792142-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020822.3(KCNT1):c.3689G>T(p.Arg1230Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,670 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1230G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KCNT1
NM_020822.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.37

Publications

0 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:

LOC107987140 (HGNC:):

LOC107987140 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNT1	NM_020822.3 link	c.3689G>T	p.Arg1230Leu	missense_variant	Exon 31 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.3689G>T	p.Arg1230Leu	missense_variant	Exon 31 of 31	1	NM_020822.3	ENSP00000360822.2		Q5JUK3-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453670

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723400

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

86002

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111582

Other (OTH)

AF:

0.00

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.062

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

Eigen

Uncertain

0.35

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.63

D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.5

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

PhyloP100

6.4

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.8

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

REVEL

Benign

0.29

Sift

Uncertain

0.0020

.;.;D;.;.;.;.;.;.;D

Sift4G

Uncertain

0.029

D;D;D;D;D;D;D;D;D;D

Vest4

0.79

MVP

0.61

MPC

0.38

ClinPred

0.94

GERP RS

4.7

Varity_R

0.38

gMVP

0.46

Mutation Taster

=76/24

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over