chr9-135786170-C-CGCCCT

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBS1BS2

The NM_020822.3(KCNT1):c.3178-7_3178-3dupTGCCC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 3 hom., cov: 0)

Exomes 𝑓: 0.0063 ( 23 hom. )

Consequence

KCNT1
NM_020822.3 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.600

Publications

1 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 -8 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

BP6

Variant 9-135786170-C-CGCCCT is Benign according to our data. Variant chr9-135786170-C-CGCCCT is described in ClinVar as Benign. ClinVar VariationId is 196185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00574 (865/150638) while in subpopulation AMR AF = 0.00868 (132/15210). AF 95% confidence interval is 0.00747. There are 3 homozygotes in GnomAd4. There are 411 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 865 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNT1	NM_020822.3 link	c.3178-7_3178-3dupTGCCC		splice_acceptor_variant, intron_variant	Intron 28 of 30	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.3178-7_3178-3dupTGCCC		splice_acceptor_variant, intron_variant	Intron 28 of 30	1	NM_020822.3	ENSP00000360822.2		Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.00575

AC:

865

AN:

150524

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00335

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00869

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00413

Gnomad SAS

AF:

0.00253

Gnomad FIN

AF:

0.00315

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00736

Gnomad OTH

AF:

0.00727

GnomAD2 exomes

AF:

0.00488

AC:

962

AN:

197052

AF XY:

0.00464

show subpopulations

Gnomad AFR exome

AF:

0.00330

Gnomad AMR exome

AF:

0.00619

Gnomad ASJ exome

AF:

0.00331

Gnomad EAS exome

AF:

0.00414

Gnomad FIN exome

AF:

0.00274

Gnomad NFE exome

AF:

0.00601

Gnomad OTH exome

AF:

0.00593

GnomAD4 exome

AF:

0.00634

AC:

8863

AN:

1397248

Hom.:

Cov.:

AF XY:

0.00629

AC XY:

4377

AN XY:

696296

show subpopulations

African (AFR)

AF:

0.00324

AC:

AN:

30558

American (AMR)

AF:

0.00708

AC:

275

AN:

38858

Ashkenazi Jewish (ASJ)

AF:

0.00350

AC:

AN:

25144

East Asian (EAS)

AF:

0.00417

AC:

161

AN:

38610

South Asian (SAS)

AF:

0.00314

AC:

257

AN:

81932

European-Finnish (FIN)

AF:

0.00333

AC:

168

AN:

50462

Middle Eastern (MID)

AF:

0.00322

AC:

AN:

5596

European-Non Finnish (NFE)

AF:

0.00695

AC:

7428

AN:

1068114

Other (OTH)

AF:

0.00636

AC:

369

AN:

57974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

388

776

1164

1552

1940

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

278

556

834

1112

1390

<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:

0.00574

AC:

865

AN:

150638

Hom.:

Cov.:

AF XY:

0.00559

AC XY:

411

AN XY:

73584

show subpopulations

African (AFR)

AF:

0.00334

AC:

136

AN:

40752

American (AMR)

AF:

0.00868

AC:

132

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3466

East Asian (EAS)

AF:

0.00414

AC:

AN:

5068

South Asian (SAS)

AF:

0.00253

AC:

AN:

4744

European-Finnish (FIN)

AF:

0.00315

AC:

AN:

10470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00736

AC:

498

AN:

67646

Other (OTH)

AF:

0.00719

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00360

Hom.:

365

Bravo

AF:

0.00608

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 31, 2016

Eurofins Ntd Llc (ga)

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

Jul 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 14

Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jan 26, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant nocturnal frontal lobe epilepsy 5

Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.60

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over