dbSNP rs143198263: KCNT1:p.Leu998Leu (chr9-135784585-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_020822.3(KCNT1):c.2994G>A(p.Leu998Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,572,976 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L998L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 7 hom. )

Consequence

KCNT1
NM_020822.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.647

Publications

2 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: 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

new If you want to explore the variant's impact on the transcript NM_020822.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 9-135784585-G-A is Benign according to our data. Variant chr9-135784585-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.647 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.001 (147/146908) while in subpopulation AMR AF = 0.00226 (33/14580). AF 95% confidence interval is 0.00166. There are 1 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 147 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.2994G>A	p.Leu998Leu	synonymous	Exon 26 of 31	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.2859G>A	p.Leu953Leu	synonymous	Exon 25 of 31	NP_001258932.1	Q5JUK3-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNT1	ENST00000371757.7	TSL:1 MANE Select	c.2994G>A	p.Leu998Leu	synonymous	Exon 26 of 31	ENSP00000360822.2	Q5JUK3-3
KCNT1	ENST00000460750.5	TSL:1	n.*2604G>A		non_coding_transcript_exon	Exon 26 of 32	ENSP00000418777.1	F8WC49
KCNT1	ENST00000460750.5	TSL:1	n.*2604G>A		3_prime_UTR	Exon 26 of 32	ENSP00000418777.1	F8WC49

Frequencies

GnomAD3 genomes

AF:

0.00100

AC:

147

AN:

146784

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000278

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00227

Gnomad ASJ

AF:

0.000875

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00133

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0367

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.00446

GnomAD2 exomes

AF:

0.00129

AC:

313

AN:

243214

AF XY:

0.00133

show subpopulations

Gnomad AFR exome

AF:

0.0000652

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.00132

Gnomad EAS exome

AF:

0.0000551

Gnomad FIN exome

AF:

0.0000490

Gnomad NFE exome

AF:

0.00156

Gnomad OTH exome

AF:

0.00373

GnomAD4 exome

AF:

0.00113

AC:

1612

AN:

1426068

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

800

AN XY:

709094

show subpopulations

African (AFR)

AF:

0.00109

AC:

AN:

31968

American (AMR)

AF:

0.00275

AC:

120

AN:

43712

Ashkenazi Jewish (ASJ)

AF:

0.000838

AC:

AN:

25054

East Asian (EAS)

AF:

0.0000269

AC:

AN:

37192

South Asian (SAS)

AF:

0.000842

AC:

AN:

85546

European-Finnish (FIN)

AF:

0.000103

AC:

AN:

48626

Middle Eastern (MID)

AF:

0.0249

AC:

111

AN:

4462

European-Non Finnish (NFE)

AF:

0.000995

AC:

1086

AN:

1091482

Other (OTH)

AF:

0.00277

AC:

161

AN:

58026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

160

241

321

401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00100

AC:

147

AN:

146908

Hom.:

Cov.:

AF XY:

0.000910

AC XY:

AN XY:

71390

show subpopulations

African (AFR)

AF:

0.000277

AC:

AN:

39714

American (AMR)

AF:

0.00226

AC:

AN:

14580

Ashkenazi Jewish (ASJ)

AF:

0.000875

AC:

AN:

3428

East Asian (EAS)

AF:

0.00

AC:

AN:

4778

South Asian (SAS)

AF:

0.00133

AC:

AN:

4512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9546

Middle Eastern (MID)

AF:

0.0393

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.00110

AC:

AN:

67144

Other (OTH)

AF:

0.00442

AC:

AN:

2038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.00147

Hom.:

Bravo

AF:

0.00151

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)

Developmental and epileptic encephalopathy, 14 (1)

Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

4.9

(source)

DANN

Benign

0.77

PhyloP100

-0.65

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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