NM_020822.3:c.3178-12_3178-3dupTGCCCTGCCC

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.3178-12_3178-3dupTGCCCTGCCC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00033 ( 2 hom. )

Consequence

KCNT1
NM_020822.3 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Likely 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
malignant migrating partial seizures of infancy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
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-CGCCCTGCCCT is Benign according to our data. Variant chr9-135786170-C-CGCCCTGCCCT is described in ClinVar as Likely_benign. ClinVar VariationId is 421819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000518 (78/150642) while in subpopulation EAS AF = 0.00118 (6/5068). AF 95% confidence interval is 0.00053. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 78 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	NM_020822.3	MANE Select	c.3178-12_3178-3dupTGCCCTGCCC		splice_acceptor intron	N/A	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.3043-12_3043-3dupTGCCCTGCCC		splice_acceptor intron	N/A	NP_001258932.1	Q5JUK3-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KCNT1	ENST00000371757.7	TSL:1 MANE Select	c.3178-12_3178-3dupTGCCCTGCCC	splice_acceptor intron	N/A	ENSP00000360822.2	Q5JUK3-3
KCNT1	ENST00000460750.5	TSL:1	n.2788-12_2788-3dupTGCCCTGCCC	splice_acceptor intron	N/A	ENSP00000418777.1	F8WC49
KCNT1	ENST00000487664.5	TSL:5	c.3178-12_3178-3dupTGCCCTGCCC	splice_acceptor intron	N/A	ENSP00000417851.2	Q5JUK3-2

Frequencies

GnomAD3 genomes

AF:

0.000525

AC:

AN:

150528

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000738

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000395

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00118

Gnomad SAS

AF:

0.000842

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000414

Gnomad OTH

AF:

0.000969

GnomAD2 exomes

AF:

0.000401

AC:

AN:

197052

AF XY:

0.000420

show subpopulations

Gnomad AFR exome

AF:

0.000388

Gnomad AMR exome

AF:

0.000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00104

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000414

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000331

AC:

462

AN:

1397630

Hom.:

Cov.:

AF XY:

0.000356

AC XY:

248

AN XY:

696464

show subpopulations

African (AFR)

AF:

0.000327

AC:

AN:

30558

American (AMR)

AF:

0.000360

AC:

AN:

38862

Ashkenazi Jewish (ASJ)

AF:

0.0000398

AC:

AN:

25146

East Asian (EAS)

AF:

0.000932

AC:

AN:

38610

South Asian (SAS)

AF:

0.000452

AC:

AN:

81936

European-Finnish (FIN)

AF:

0.0000198

AC:

AN:

50462

Middle Eastern (MID)

AF:

0.000536

AC:

AN:

5596

European-Non Finnish (NFE)

AF:

0.000315

AC:

337

AN:

1068466

Other (OTH)

AF:

0.000397

AC:

AN:

57994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.411

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000518

AC:

AN:

150642

Hom.:

Cov.:

AF XY:

0.000462

AC XY:

AN XY:

73586

show subpopulations

African (AFR)

AF:

0.000736

AC:

AN:

40752

American (AMR)

AF:

0.000394

AC:

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3466

East Asian (EAS)

AF:

0.00118

AC:

AN:

5068

South Asian (SAS)

AF:

0.000843

AC:

AN:

4744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10472

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000399

AC:

AN:

67648

Other (OTH)

AF:

0.000959

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000313

Hom.:

365

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)

Developmental and epileptic encephalopathy, 14 (1)

KCNT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over