rs61744696

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_020822.3(KCNT1):c.2210C>T(p.Thr737Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,529,262 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T737T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 22 hom., cov: 33)

Exomes 𝑓: 0.015 ( 190 hom. )

Consequence

KCNT1
NM_020822.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.69

Publications

9 publications found

Variant links:

COSMIC-nc: COSV107221927

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 -16 ACMG points.

BP6

Variant 9-135772916-C-T is Benign according to our data. Variant chr9-135772916-C-T is described in ClinVar as Benign. ClinVar VariationId is 129356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.012 (1826/152294) while in subpopulation NFE AF = 0.0173 (1175/68024). AF 95% confidence interval is 0.0165. There are 22 homozygotes in GnomAd4. There are 886 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1826 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.2210C>T	p.Thr737Met	missense	Exon 19 of 31	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.2075C>T	p.Thr692Met	missense	Exon 18 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.2210C>T	p.Thr737Met	missense	Exon 19 of 31	ENSP00000360822.2	Q5JUK3-3
KCNT1	ENST00000460750.5	TSL:1	n.*1820C>T		non_coding_transcript_exon	Exon 19 of 32	ENSP00000418777.1	F8WC49
KCNT1	ENST00000460750.5	TSL:1	n.*1820C>T		3_prime_UTR	Exon 19 of 32	ENSP00000418777.1	F8WC49

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1826

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00297

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.00894

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0276

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0173

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0123

AC:

1673

AN:

136438

AF XY:

0.0121

show subpopulations

Gnomad AFR exome

AF:

0.00319

Gnomad AMR exome

AF:

0.00909

Gnomad ASJ exome

AF:

0.0122

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0283

Gnomad NFE exome

AF:

0.0175

Gnomad OTH exome

AF:

0.0130

GnomAD4 exome

AF:

0.0152

AC:

20987

AN:

1376968

Hom.:

190

Cov.:

AF XY:

0.0148

AC XY:

10060

AN XY:

678806

show subpopulations

African (AFR)

AF:

0.00217

AC:

AN:

30940

American (AMR)

AF:

0.0101

AC:

318

AN:

31604

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

257

AN:

23574

East Asian (EAS)

AF:

0.0000559

AC:

AN:

35776

South Asian (SAS)

AF:

0.00126

AC:

AN:

75664

European-Finnish (FIN)

AF:

0.0269

AC:

1205

AN:

44756

Middle Eastern (MID)

AF:

0.00545

AC:

AN:

5502

European-Non Finnish (NFE)

AF:

0.0170

AC:

18212

AN:

1072192

Other (OTH)

AF:

0.0141

AC:

801

AN:

56960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1052

2103

3155

4206

5258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

662

1324

1986

2648

3310

<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:

0.0120

AC:

1826

AN:

152294

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

886

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00296

AC:

123

AN:

41566

American (AMR)

AF:

0.0108

AC:

166

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00894

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0276

AC:

293

AN:

10612

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0173

AC:

1175

AN:

68024

Other (OTH)

AF:

0.0123

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

179

268

358

447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0146

Hom.:

Bravo

AF:

0.0112

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.00410

AC:

ESP6500EA

AF:

0.0153

AC:

131

ExAC

AF:

0.00814

AC:

959

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

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 provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.073

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.9

PhyloP100

1.7

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.1

REVEL

Benign

0.23

Sift

Benign

0.082

Sift4G

Benign

0.097

Polyphen

0.11

Vest4

0.35

MPC

0.67

ClinPred

0.0068

GERP RS

3.0

Varity_R

0.061

gMVP

0.40

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: -5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over