9-135792141-C-G

Variant names:

• chr9-135792141-C-G
• rs771068120
• NM_020822.3:c.3688C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020822.3(KCNT1):​c.3688C>G​(p.Arg1230Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R1230H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.93
• 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

LOC107987140 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNT1	NM_020822.3	c.3688C>G	p.Arg1230Gly	missense_variant	Exon 31 of 31	ENST00000371757.7	NP_065873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7	c.3688C>G	p.Arg1230Gly	missense_variant	Exon 31 of 31	1	NM_020822.3	ENSP00000360822.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Mar 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1230 of the KCNT1 protein (p.Arg1230Gly). This variant has not been reported in the literature in individuals affected with KCNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2433044). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNT1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Sep 28, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	.;.;.;.;.;.;.;.;T;.
Eigen	Benign	0.098
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.5	.;.;.;.;.;.;.;.;L;.
PhyloP100		1.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	.;.;D;.;.;.;.;.;.;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	.;.;D;.;.;.;.;.;.;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D
Vest4		0.80
MVP		0.59
MPC		0.13
ClinPred		0.77	D
GERP RS		2.7
Varity_R		0.37
gMVP		0.48
Mutation Taster		=68/32	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: rs771068120; hg19: chr9-138683987;