rs200250181

Variant names:

• chr9-135786258-G-T
• rs200250181
• NM_020822.3:c.3239G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020822.3(KCNT1):​c.3239G>T​(p.Gly1080Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,610,928 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. G1080G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (8 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.55
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059975684).
• BP6: Variant 9-135786258-G-T is Benign according to our data. Variant chr9-135786258-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 385356.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 = 0.00152 (231/152120) while in subpopulation NFE AF = 0.00255 (173/67932). AF 95% confidence interval is 0.00224. There are 2 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 231 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.3239G>T	p.Gly1080Val	missense	Exon 29 of 31	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.3104G>T	p.Gly1035Val	missense	Exon 28 of 31	NP_001258932.1	Q5JUK3-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	ENST00000371757.7	TSL:1 MANE Select	c.3239G>T	p.Gly1080Val	missense	Exon 29 of 31	ENSP00000360822.2	Q5JUK3-3
	KCNT1	ENST00000460750.5	TSL:1	n.*2849G>T		non_coding_transcript_exon	Exon 29 of 32	ENSP00000418777.1	F8WC49
	KCNT1	ENST00000460750.5	TSL:1	n.*2849G>T		3_prime_UTR	Exon 29 of 32	ENSP00000418777.1	F8WC49

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 231 AN: 152006 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00255

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00186 AC: 434 AN: 233102 AF XY: 0.00195

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000412

Gnomad ASJ exome AF: 0.00470

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.00309

Gnomad OTH exome AF: 0.00174

GnomAD4 exome AF: 0.00260 AC: 3799 AN: 1458808 Hom.: 8 Cov.: 36 AF XY: 0.00255 AC XY: 1849 AN XY: 725654

African (AFR) AF: 0.000419 AC: 14 AN: 33448

American (AMR) AF: 0.000314 AC: 14 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00326 AC: 85 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00156 AC: 134 AN: 86010

European-Finnish (FIN) AF: 0.000542 AC: 28 AN: 51694

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5752

European-Non Finnish (NFE) AF: 0.00306 AC: 3404 AN: 1111376

Other (OTH) AF: 0.00188 AC: 113 AN: 60220

GnomAD4 genome AF: 0.00152 AC: 231 AN: 152120 Hom.: 2 Cov.: 33 AF XY: 0.00125 AC XY: 93 AN XY: 74398

African (AFR) AF: 0.000506 AC: 21 AN: 41520

American (AMR) AF: 0.000719 AC: 11 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00255 AC: 173 AN: 67932

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00217 Hom.: 1

Bravo AF: 0.00159

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000241 AC: 1

ESP6500EA AF: 0.00222 AC: 18

ExAC AF: 0.00187 AC: 223

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00149

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)
-	-	1	Developmental and epileptic encephalopathy, 14 (1)
-	-	1	Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	KCNT1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.60
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.045
Sift	Uncertain	0.010	D
Sift4G	Benign	0.33	T
Vest4		0.20
MVP		0.35
MPC		0.11
ClinPred		0.031	T
GERP RS		0.83
Varity_R		0.11
gMVP		0.49
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs200250181; hg19: chr9-138678104;