9-135765033-C-G

Variant names:

• chr9-135765033-C-G
• rs767434859
• NM_020822.3:c.1038C>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_020822.3(KCNT1):​c.1038C>G​(p.Phe346Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F346F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNT1 NM_020822.3 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.872
• Publications: 2 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 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_020822.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-135765033-C-G is Pathogenic according to our data. Variant chr9-135765033-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 853550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNT1	NM_020822.3	c.1038C>G	p.Phe346Leu	missense_variant, splice_region_variant	Exon 12 of 31	ENST00000371757.7	NP_065873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7	c.1038C>G	p.Phe346Leu	missense_variant, splice_region_variant	Exon 12 of 31	1	NM_020822.3	ENSP00000360822.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 Pathogenic:1

Jul 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNT1 function (PMID: 29196579). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 346 of the KCNT1 protein (p.Phe346Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 30868116, 31618474; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 853550). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Uncertain	0.55	.;.;.;.;.;.;.;.;D;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.10	.;.;.;.;.;.;.;.;N;.
PhyloP100		-0.87
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.6	.;.;D;D;.;.;.;.;D;D
REVEL	Benign	0.22
Sift	Benign	0.34	.;.;T;T;.;.;.;.;T;T
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T;T;T
Polyphen		0.036	.;.;.;.;.;.;.;.;B;.
Vest4		0.79
MutPred		0.54		.;.;.;.;.;.;Gain of catalytic residue at F327 (P = 0.2065);Gain of catalytic residue at F327 (P = 0.2065);Gain of catalytic residue at F327 (P = 0.2065);Gain of catalytic residue at F327 (P = 0.2065);
MVP		0.22
MPC		0.90
ClinPred		0.44	T
GERP RS		-2.4
Varity_R		0.45
gMVP		0.88
Mutation Taster		=39/61	disease causing (ClinVar)

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: rs767434859; hg19: chr9-138656879;