chr9-135750176-G-A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_020822.3(KCNT1):​c.333G>A​(p.Ser111Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,612,892 control chromosomes in the GnomAD database, including 9 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 0.0027 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0044 ( 9 hom. )

Consequence

KCNT1
NM_020822.3 splice_region, synonymous

Scores

2
Splicing: ADA: 0.00004513
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.557

Publications

3 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.33).
BP6
Variant 9-135750176-G-A is Benign according to our data. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135750176-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 196503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.557 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0027 (410/152018) while in subpopulation NFE AF = 0.00472 (321/67960). AF 95% confidence interval is 0.0043. There are 0 homozygotes in GnomAd4. There are 183 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAd4 at 410 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNT1NM_020822.3 linkc.333G>A p.Ser111Ser splice_region_variant, synonymous_variant Exon 3 of 31 ENST00000371757.7 NP_065873.2 Q5JUK3-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNT1ENST00000371757.7 linkc.333G>A p.Ser111Ser splice_region_variant, synonymous_variant Exon 3 of 31 1 NM_020822.3 ENSP00000360822.2 Q5JUK3-3

Frequencies

GnomAD3 genomes
AF:
0.00270
AC:
410
AN:
151900
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000943
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00131
Gnomad ASJ
AF:
0.00720
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000416
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00472
Gnomad OTH
AF:
0.000956
GnomAD2 exomes
AF:
0.00248
AC:
621
AN:
250186
AF XY:
0.00266
show subpopulations
Gnomad AFR exome
AF:
0.00130
Gnomad AMR exome
AF:
0.000493
Gnomad ASJ exome
AF:
0.00629
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000186
Gnomad NFE exome
AF:
0.00433
Gnomad OTH exome
AF:
0.00262
GnomAD4 exome
AF:
0.00437
AC:
6381
AN:
1460874
Hom.:
9
Cov.:
31
AF XY:
0.00422
AC XY:
3065
AN XY:
726762
show subpopulations
African (AFR)
AF:
0.000837
AC:
28
AN:
33464
American (AMR)
AF:
0.000559
AC:
25
AN:
44706
Ashkenazi Jewish (ASJ)
AF:
0.00750
AC:
196
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.000464
AC:
40
AN:
86230
European-Finnish (FIN)
AF:
0.000301
AC:
16
AN:
53080
Middle Eastern (MID)
AF:
0.000347
AC:
2
AN:
5766
European-Non Finnish (NFE)
AF:
0.00527
AC:
5855
AN:
1111454
Other (OTH)
AF:
0.00363
AC:
219
AN:
60348
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.474
Heterozygous variant carriers
0
287
575
862
1150
1437
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
232
464
696
928
1160
<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:
0.00270
AC:
410
AN:
152018
Hom.:
0
Cov.:
32
AF XY:
0.00246
AC XY:
183
AN XY:
74298
show subpopulations
African (AFR)
AF:
0.000941
AC:
39
AN:
41464
American (AMR)
AF:
0.00131
AC:
20
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00720
AC:
25
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5136
South Asian (SAS)
AF:
0.000417
AC:
2
AN:
4800
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10584
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.00472
AC:
321
AN:
67960
Other (OTH)
AF:
0.000946
AC:
2
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.495
Heterozygous variant carriers
0
24
48
72
96
120
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
10
20
30
40
50
<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:
0.00409
Hom.:
7
Bravo
AF:
0.00285
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00409
EpiControl
AF:
0.00427

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Apr 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

KCNT1: BP4, BP7 -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not specified Benign:4
Dec 02, 2024
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 28, 2015
Eurofins Ntd Llc (ga)
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 03, 2015
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 22, 2016
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

- -

Inborn genetic diseases Benign:1
Oct 05, 2016
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

- -

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
BayesDel_noAF
Benign
-0.33
CADD
Benign
16
DANN
Benign
0.75
PhyloP100
0.56
Mutation Taster
=77/23
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000045
dbscSNV1_RF
Benign
0.022
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

Other links and lift over

dbSNP: rs56008253; hg19: chr9-138642022; COSMIC: COSV53703333; COSMIC: COSV53703333; API