rs559344618

Variant names:

Variant summary

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

The ENST00000371757.7(KCNT1):c.2236G>A(p.Val746Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000706 in 1,488,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict 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. V746V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

KCNT1
ENST00000371757.7 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.45

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 -16 ACMG points.

BP6

Variant 9-135772942-G-A is Benign according to our data. Variant chr9-135772942-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 386181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000204 (31/152312) while in subpopulation AMR AF = 0.00183 (28/15306). AF 95% confidence interval is 0.0013. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 31 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000371757.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	NM_020822.3	MANE Select	c.2236G>A	p.Val746Met	missense	Exon 19 of 31	NP_065873.2
	KCNT1	NM_001272003.2		c.2101G>A	p.Val701Met	missense	Exon 18 of 31	NP_001258932.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNT1	ENST00000371757.7	TSL:1 MANE Select	c.2236G>A	p.Val746Met	missense	Exon 19 of 31	ENSP00000360822.2
KCNT1	ENST00000460750.5	TSL:1	n.*1846G>A		non_coding_transcript_exon	Exon 19 of 32	ENSP00000418777.1
KCNT1	ENST00000460750.5	TSL:1	n.*1846G>A		3_prime_UTR	Exon 19 of 32	ENSP00000418777.1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000221

AC:

AN:

99470

AF XY:

0.000209

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000354

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1335986

Hom.:

Cov.:

AF XY:

0.0000627

AC XY:

AN XY:

654028

show subpopulations

African (AFR)

AF:

0.0000668

AC:

AN:

29958

American (AMR)

AF:

0.00172

AC:

AN:

27364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21700

East Asian (EAS)

AF:

0.00

AC:

AN:

34482

South Asian (SAS)

AF:

0.0000142

AC:

AN:

70208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5234

European-Non Finnish (NFE)

AF:

0.0000200

AC:

AN:

1052118

Other (OTH)

AF:

0.0000542

AC:

AN:

55380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000204

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41566

American (AMR)

AF:

0.00183

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.000402

Hom.:

Bravo

AF:

0.000170

ExAC

AF:

0.0000263

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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)

KCNT1-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.036

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0069

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.69

PhyloP100

2.4

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.39

REVEL

Benign

0.12

Sift

Benign

0.14

Sift4G

Benign

0.27

Polyphen

0.0030

Vest4

0.25

MVP

0.52

MPC

0.80

ClinPred

0.019

GERP RS

0.89

Varity_R

0.033

gMVP

0.38

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.28

Position offset: 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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over