9-135770463-A-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.1769+16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 1,600,964 control chromosomes in the GnomAD database, including 407,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.72 ( 39790 hom., cov: 36)

Exomes 𝑓: 0.71 ( 367946 hom. )

Consequence

KCNT1
NM_020822.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.457

Publications

13 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=-0.88).

BP6

Variant 9-135770463-A-G is Benign according to our data. Variant chr9-135770463-A-G is described in ClinVar as Benign. ClinVar VariationId is 194782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.774 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.1769+16A>G		intron	N/A	NP_065873.2
	KCNT1	NM_001272003.2		c.1634+16A>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.1769+16A>G	intron	N/A	ENSP00000360822.2
KCNT1	ENST00000460750.5	TSL:1	n.*1379+16A>G	intron	N/A	ENSP00000418777.1
KCNT1	ENST00000487664.5	TSL:5	c.1769+16A>G	intron	N/A	ENSP00000417851.2

Frequencies

GnomAD3 genomes

AF:

0.721

AC:

109650

AN:

152070

Hom.:

39746

Cov.:

show subpopulations

Gnomad AFR

AF:

0.771

Gnomad AMI

AF:

0.663

Gnomad AMR

AF:

0.658

Gnomad ASJ

AF:

0.590

Gnomad EAS

AF:

0.712

Gnomad SAS

AF:

0.795

Gnomad FIN

AF:

0.746

Gnomad MID

AF:

0.627

Gnomad NFE

AF:

0.706

Gnomad OTH

AF:

0.675

GnomAD2 exomes

AF:

0.707

AC:

168006

AN:

237642

AF XY:

0.710

show subpopulations

Gnomad AFR exome

AF:

0.776

Gnomad AMR exome

AF:

0.638

Gnomad ASJ exome

AF:

0.587

Gnomad EAS exome

AF:

0.707

Gnomad FIN exome

AF:

0.744

Gnomad NFE exome

AF:

0.701

Gnomad OTH exome

AF:

0.687

GnomAD4 exome

AF:

0.712

AC:

1031260

AN:

1448772

Hom.:

367946

Cov.:

AF XY:

0.714

AC XY:

513611

AN XY:

719634

show subpopulations

African (AFR)

AF:

0.778

AC:

25897

AN:

33302

American (AMR)

AF:

0.638

AC:

27975

AN:

43826

Ashkenazi Jewish (ASJ)

AF:

0.593

AC:

14885

AN:

25090

East Asian (EAS)

AF:

0.704

AC:

27905

AN:

39642

South Asian (SAS)

AF:

0.783

AC:

65553

AN:

83746

European-Finnish (FIN)

AF:

0.745

AC:

38857

AN:

52150

Middle Eastern (MID)

AF:

0.644

AC:

3668

AN:

5698

European-Non Finnish (NFE)

AF:

0.710

AC:

784845

AN:

1105432

Other (OTH)

AF:

0.696

AC:

41675

AN:

59886

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

14426

28852

43278

57704

72130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19848

39696

59544

79392

99240

<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:

0.721

AC:

109750

AN:

152192

Hom.:

39790

Cov.:

AF XY:

0.722

AC XY:

53687

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.771

AC:

32024

AN:

41516

American (AMR)

AF:

0.658

AC:

10071

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.590

AC:

2050

AN:

3472

East Asian (EAS)

AF:

0.712

AC:

3675

AN:

5162

South Asian (SAS)

AF:

0.795

AC:

3837

AN:

4826

European-Finnish (FIN)

AF:

0.746

AC:

7912

AN:

10610

Middle Eastern (MID)

AF:

0.626

AC:

184

AN:

294

European-Non Finnish (NFE)

AF:

0.705

AC:

47961

AN:

67984

Other (OTH)

AF:

0.678

AC:

1431

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1656

3312

4968

6624

8280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

850

1700

2550

3400

4250

<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:

0.697

Hom.:

57367

Bravo

AF:

0.710

Asia WGS

AF:

0.771

AC:

2684

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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 86% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 80. Only high quality variants are reported.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 04, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

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

-0.88

CADD

Benign

1.7

(source)

DANN

Benign

0.29

PhyloP100

-0.46

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