rs371874401

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020822.3(KCNT1):c.3157-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,612,950 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

KCNT1
NM_020822.3 splice_region, intron

Scores

Splicing: ADA: 0.00001683

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.147

Publications

0 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=-0.86).

BP6

Variant 9-135785302-C-T is Benign according to our data. Variant chr9-135785302-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000866 (132/152354) while in subpopulation AFR AF = 0.00303 (126/41586). AF 95% confidence interval is 0.0026. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 132 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNT1	NM_020822.3 link	c.3157-8C>T		splice_region_variant, intron_variant	Intron 27 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.3157-8C>T		splice_region_variant, intron_variant	Intron 27 of 30	1	NM_020822.3	ENSP00000360822.2		Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

133

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00306

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00144

GnomAD2 exomes

AF:

0.000285

AC:

AN:

249368

AF XY:

0.000222

show subpopulations

Gnomad AFR exome

AF:

0.00422

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000103

AC:

151

AN:

1460596

Hom.:

Cov.:

AF XY:

0.0000950

AC XY:

AN XY:

726614

show subpopulations

African (AFR)

AF:

0.00400

AC:

134

AN:

33476

American (AMR)

AF:

0.0000671

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111884

Other (OTH)

AF:

0.000166

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

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:

0.000866

AC:

132

AN:

152354

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00303

AC:

126

AN:

41586

American (AMR)

AF:

0.000196

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000604

Hom.:

Bravo

AF:

0.00102

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jan 07, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 14, 2016

Eurofins Ntd Llc (ga)

Significance:Likely 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

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KCNT1-related disorder

Benign:1

Jul 25, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Developmental and epileptic encephalopathy, 14

Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 02, 2020

GeneDx

Significance:Likely 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

8.4

(source)

DANN

Benign

0.63

PhyloP100

-0.15

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000017

dbscSNV1_RF

Benign

0.0080

SpliceAI score (max)

0.10

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over