rs756952430

Positions:

chr9-135757181-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4BP6_Very_StrongBS2

The NM_020822.3(KCNT1):c.626G>A(p.Arg209His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,455,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R209C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000016 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNT1
NM_020822.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.24

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:

KCNT1 (HGNC:):

KCNT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.41640145).

BP6

Variant 9-135757181-G-A is Benign according to our data. Variant chr9-135757181-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 574245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3 linkuse as main transcript	c.626G>A	p.Arg209His	missense_variant	8/31	ENST00000371757.7	NP_065873.2	Q5JUK3-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7 linkuse as main transcript	c.626G>A	p.Arg209His	missense_variant	8/31	1	NM_020822.3	ENSP00000360822.2		Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

138936

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250854

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1455600

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

724054

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000508

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000631

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

138936

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

66422

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 08, 2022

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2019

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.062

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

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.74

MetaRNN

Benign

0.42

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

MetaSVM

Uncertain

0.43

MutationAssessor

Benign

1.8

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

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.86

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

REVEL

Benign

0.076

Sift

Benign

0.21

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

Sift4G

Benign

0.16

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

Vest4

0.22

MutPred

0.63

.;.;.;.;.;.;Loss of catalytic residue at R176 (P = 0.0657);.;.;.;.;

MVP

0.85

MPC

0.79

ClinPred

0.40

GERP RS

0.68

Varity_R

0.045

gMVP

0.75

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

Other links and lift over