9-135714665-C-T

Variant names:

• chr9-135714665-C-T
• rs1060503698
• NM_020822.3:c.199C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020822.3(KCNT1):​c.199C>T​(p.Arg67Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000225 in 1,335,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R67P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.628
• 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3181976).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	NM_020822.3	MANE Select	c.199C>T	p.Arg67Cys	missense	Exon 2 of 31	NP_065873.2
	KCNT1	NM_001272003.2		c.110+12297C>T		intron	N/A	NP_001258932.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	ENST00000371757.7	TSL:1 MANE Select	c.199C>T	p.Arg67Cys	missense	Exon 2 of 31	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.199C>T		non_coding_transcript_exon	Exon 2 of 32	ENSP00000418777.1
	KCNT1	ENST00000487664.5	TSL:5	c.199C>T	p.Arg67Cys	missense	Exon 2 of 32	ENSP00000417851.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 181606 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000225 AC: 3 AN: 1335940 Hom.: 0 Cov.: 30 AF XY: 0.00000150 AC XY: 1 AN XY: 664822

African (AFR) AF: 0.00 AC: 0 AN: 26808

American (AMR) AF: 0.00 AC: 0 AN: 35408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21716

East Asian (EAS) AF: 0.00 AC: 0 AN: 28434

South Asian (SAS) AF: 0.00 AC: 0 AN: 77796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5100

European-Non Finnish (NFE) AF: 0.00000288 AC: 3 AN: 1041900

Other (OTH) AF: 0.00 AC: 0 AN: 52576

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	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	Pathogenic	0.90
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Benign	0.10
Eigen_PC	Benign	0.011
FATHMM_MKL	Benign	0.053	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.63
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.24
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0030	D
Vest4		0.61
MutPred		0.40		Loss of helix (P = 0.028)
MVP		0.39
MPC		1.9
ClinPred		0.87	D
GERP RS		2.6
PromoterAI		0.018	Neutral
gMVP		0.53
Mutation Taster		=90/10	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: rs1060503698; hg19: chr9-138606511;