chr9-135778780-T-G

Position:

• chr9-135778780-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_020822.3(KCNT1):​c.2687T>G​(p.Met896Arg) variant causes a missense change. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M896I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.01

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-135778780-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1457517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant 9-135778780-T-G is Pathogenic according to our data. Variant chr9-135778780-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 412308.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.2687T>G	p.Met896Arg	missense_variant	23/31	ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.2687T>G	p.Met896Arg	missense_variant	23/31	1	NM_020822.3	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 05, 2017

This sequence change replaces methionine with arginine at codon 896 of the KCNT1 protein (p.Met896Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNT1-related disease. However, family studies have indicated that this variant was not present in the parents of an individual with KCNT1-related disease, which suggests that it was de novo in that affected individual (Invitae). This variant occurs  in the intracellular C-terminal region within a putative nicotinamide adeninedinucleotide (NAD+)-binding site (PMID: 19386908). A different missense substitution at this codon (p.Met896Ile) has been determined to be pathogenic (PMID: 23086396, 25482562, 24591078). In addition, a third variant (p.Met896Lys) has been reported de novo in an individual affected with early infantile epileptic encephalopathy (PMID:26993267). This suggests that the methionine residue is critical for KCNT1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	.;.;.;.;.;.;.;.;T;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.6	.;.;.;.;.;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.8	.;.;D;.;.;.;.;.;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	.;.;D;.;.;.;.;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D
Polyphen		0.98	.;.;.;.;.;.;.;.;D;.
Vest4		0.78
MutPred		0.57		.;.;.;.;.;.;Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);.;
MVP		0.89
MPC		1.8
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.93
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060503696; hg19: chr9-138670626;