9-135768848-G-T

Variant names:

• chr9-135768848-G-T
• rs397515404
• NM_020822.3:c.1421G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_020822.3(KCNT1):​c.1421G>T​(p.Arg474Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R474S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.83
• 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: 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_020822.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-135768847-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 280254.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• PP5: Variant 9-135768848-G-T is Pathogenic according to our data. Variant chr9-135768848-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1772271.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNT1	NM_020822.3	c.1421G>T	p.Arg474Leu	missense_variant	Exon 15 of 31	ENST00000371757.7	NP_065873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7	c.1421G>T	p.Arg474Leu	missense_variant	Exon 15 of 31	1	NM_020822.3	ENSP00000360822.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Mar 28, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R474L variant (also known as c.1421G>T), located in coding exon 15 of the KCNT1 gene, results from a G to T substitution at nucleotide position 1421. The arginine at codon 474 is replaced by leucine, an amino acid with dissimilar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one family with an isolated case of early infantile epileptic encephalopathy (Ambry internal data). A different alteration, located at the same position, p.R474H, has been detected as a de novo occurrence in several individuals with diagnoses of malignant migrating focal seizures of infancy (MMFSI) or intractable epilepsy (Barcia G et al. Nat. Genet., 2012 Nov;44:1255-9; Ohba C et al. Epilepsia, 2015 Sep;56:e121-8; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the p.R474L alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.090	D
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.;.;M;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.0	.;.;D;D;.;.;.;.;D;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	.;.;T;T;.;.;.;.;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Vest4		0.99
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.78
gMVP		0.99
Mutation Taster		=9/91	disease causing

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: rs397515404; hg19: chr9-138660694;