rs1554763398

Positions:

• chr9-135714706-C-G
• chr9-135714706-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000371757.7(KCNT1):​c.240C>G​(p.Phe80Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. F80F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNT1 ENST00000371757.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0780

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11178595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3	c.240C>G	p.Phe80Leu	missense_variant	2/31	ENST00000371757.7	NP_065873.2
KCNT1	XM_011518878.4	c.375C>G	p.Phe125Leu	missense_variant	2/31		XP_011517180.1
KCNT1	XM_011518879.4	c.375C>G	p.Phe125Leu	missense_variant	2/31		XP_011517181.1
KCNT1	NM_001272003.2	c.110+12338C>G		intron_variant			NP_001258932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7	c.240C>G	p.Phe80Leu	missense_variant	2/31	1	NM_020822.3	ENSP00000360822	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1292660 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 642054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 09, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 540579). This variant has not been reported in the literature in individuals affected with KCNT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 80 of the KCNT1 protein (p.Phe80Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.80	T;T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.0	.;N;D;N;.
REVEL	Benign	0.079
Sift	Benign	0.40	.;T;T;T;.
Sift4G	Benign	0.15	T;T;T;T;T
Vest4		0.30
MutPred		0.38		Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);.;.;.;
MVP		0.20
MPC		0.74
ClinPred		0.47	T
GERP RS		2.9
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554763398; hg19: chr9-138606552;