rs869312682

Variant names:

• chr9-135714602-C-T
• rs869312682
• NM_020822.3:c.136C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-135714602-C-T
• chr9-135714602-C-G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_020822.3(KCNT1):​c.136C>T​(p.Leu46Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000265 in 1,281,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.17
• Publications: 1 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09466401).
• BP6: Variant 9-135714602-C-T is Benign according to our data. Variant chr9-135714602-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 224110.
• BS2: High AC in GnomAdExome4 at 34 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.136C>T	p.Leu46Phe	missense	Exon 2 of 31	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.110+12234C>T		intron	N/A	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.136C>T	p.Leu46Phe	missense	Exon 2 of 31	ENSP00000360822.2	Q5JUK3-3
	KCNT1	ENST00000460750.5	TSL:1	n.136C>T		non_coding_transcript_exon	Exon 2 of 32	ENSP00000418777.1	F8WC49
	KCNT1	ENST00000487664.5	TSL:5	c.136C>T	p.Leu46Phe	missense	Exon 2 of 32	ENSP00000417851.2	Q5JUK3-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000265 AC: 34 AN: 1281190 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 14 AN XY: 637266

African (AFR) AF: 0.00 AC: 0 AN: 25590

American (AMR) AF: 0.00 AC: 0 AN: 32504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20020

East Asian (EAS) AF: 0.0000396 AC: 1 AN: 25232

South Asian (SAS) AF: 0.00 AC: 0 AN: 73450

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3982

European-Non Finnish (NFE) AF: 0.0000307 AC: 31 AN: 1011272

Other (OTH) AF: 0.0000407 AC: 2 AN: 49132

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000379 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 14 (1)
-	1	-	Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Uncertain	0.98
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.98	T
PhyloP100		2.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.053
Sift	Benign	0.22	T
Sift4G	Uncertain	0.044	D
Vest4		0.097
MutPred		0.18		Gain of catalytic residue at L46 (P = 0.0236)
MVP		0.081
MPC		0.69
ClinPred		0.66	D
GERP RS		2.7
PromoterAI		0.080	Neutral
gMVP		0.17
Mutation Taster		=98/2	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: rs869312682; hg19: chr9-138606448;