9-135765207-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020822.3(KCNT1):c.1200+12T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,603,724 control chromosomes in the GnomAD database, including 44,104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4132 hom., cov: 32)

Exomes 𝑓: 0.23 ( 39972 hom. )

Consequence

KCNT1
NM_020822.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.95

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 9-135765207-T-G is Benign according to our data. Variant chr9-135765207-T-G is described in ClinVar as Benign. ClinVar VariationId is 261361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020822.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	NM_020822.3	MANE Select	c.1200+12T>G		intron	N/A	NP_065873.2
	KCNT1	NM_001272003.2		c.1065+12T>G		intron	N/A	NP_001258932.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
KCNT1	ENST00000371757.7	TSL:1 MANE Select	c.1200+12T>G	intron	N/A	ENSP00000360822.2
KCNT1	ENST00000460750.5	TSL:1	n.*810+12T>G	intron	N/A	ENSP00000418777.1
KCNT1	ENST00000487664.5	TSL:5	c.1200+12T>G	intron	N/A	ENSP00000417851.2

Frequencies

GnomAD3 genomes

AF:

0.229

AC:

34814

AN:

151764

Hom.:

4129

Cov.:

show subpopulations

Gnomad AFR

AF:

0.248

Gnomad AMI

AF:

0.289

Gnomad AMR

AF:

0.253

Gnomad ASJ

AF:

0.289

Gnomad EAS

AF:

0.0398

Gnomad SAS

AF:

0.169

Gnomad FIN

AF:

0.164

Gnomad MID

AF:

0.330

Gnomad NFE

AF:

0.237

Gnomad OTH

AF:

0.244

GnomAD2 exomes

AF:

0.216

AC:

53898

AN:

250026

AF XY:

0.214

show subpopulations

Gnomad AFR exome

AF:

0.245

Gnomad AMR exome

AF:

0.258

Gnomad ASJ exome

AF:

0.278

Gnomad EAS exome

AF:

0.0401

Gnomad FIN exome

AF:

0.162

Gnomad NFE exome

AF:

0.242

Gnomad OTH exome

AF:

0.250

GnomAD4 exome

AF:

0.230

AC:

333576

AN:

1451842

Hom.:

39972

Cov.:

AF XY:

0.228

AC XY:

164498

AN XY:

720344

show subpopulations

African (AFR)

AF:

0.249

AC:

8294

AN:

33314

American (AMR)

AF:

0.258

AC:

11491

AN:

44574

Ashkenazi Jewish (ASJ)

AF:

0.279

AC:

7245

AN:

26010

East Asian (EAS)

AF:

0.0331

AC:

1305

AN:

39442

South Asian (SAS)

AF:

0.170

AC:

14664

AN:

86046

European-Finnish (FIN)

AF:

0.167

AC:

8742

AN:

52416

Middle Eastern (MID)

AF:

0.324

AC:

1860

AN:

5736

European-Non Finnish (NFE)

AF:

0.241

AC:

266110

AN:

1104352

Other (OTH)

AF:

0.231

AC:

13865

AN:

59952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

12801

25602

38402

51203

64004

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9048

18096

27144

36192

45240

<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:

0.229

AC:

34837

AN:

151882

Hom.:

4132

Cov.:

AF XY:

0.225

AC XY:

16679

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.249

AC:

10290

AN:

41376

American (AMR)

AF:

0.253

AC:

3861

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.289

AC:

1003

AN:

3466

East Asian (EAS)

AF:

0.0397

AC:

205

AN:

5160

South Asian (SAS)

AF:

0.169

AC:

813

AN:

4814

European-Finnish (FIN)

AF:

0.164

AC:

1735

AN:

10594

Middle Eastern (MID)

AF:

0.331

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.237

AC:

16064

AN:

67902

Other (OTH)

AF:

0.241

AC:

507

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1372

2745

4117

5490

6862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.232

Hom.:

1776

Bravo

AF:

0.237

Asia WGS

AF:

0.121

AC:

421

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 51% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 47. Only high quality variants are reported.

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 30, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Developmental and epileptic encephalopathy, 14

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal dominant nocturnal frontal lobe epilepsy 5

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

1.2

(source)

DANN

Benign

0.33

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over