Variant 9-135765061-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_020822.3(KCNT1):c.1066C>T(p.Arg356Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KCNT1
NM_020822.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 1.74

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.807

PP5

Variant 9-135765061-C-T is Pathogenic according to our data. Variant chr9-135765061-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 389450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3 linkuse as main transcript	c.1066C>T	p.Arg356Trp	missense_variant	12/31	ENST00000371757.7	NP_065873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7 linkuse as main transcript	c.1066C>T	p.Arg356Trp	missense_variant	12/31	1	NM_020822.3	ENSP00000360822	A2	Q5JUK3-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460568

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726538

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2022	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 389450). This missense change has been observed in individual(s) with KCNT1-related conditions (PMID: 25326635, 31532594; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 356 of the KCNT1 protein (p.Arg356Trp). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 31, 2017	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2022	Reported in a patient in published literature with infantile seizures who also harbored another variant in the KCNT1 gene, although familial segregation information was not provided to determine if either variant occurred de novo or to determine if the variants occurred on the same (in cis) or on different (in trans) chromosomes (Passey et al., 2019); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31532594, 31216405, 31388363, 31618474, 32776321, 25326635, 34074526) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2018	- -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 08, 2019

ACMG classification criteria: PS2, PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Benign

0.0014

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

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

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

1.0

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

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.81

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

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.5

.;.;.;.;.;.;.;.;M;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.4

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

REVEL

Benign

0.26

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.74

MutPred

0.53

.;.;.;.;.;.;Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);Loss of disorder (P = 0.0179);

MVP

0.63

MPC

1.7

ClinPred

1.0

GERP RS

3.2

Varity_R

0.85

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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