rs770986306

Variant names:

• chr9-135770315-C-T
• rs770986306
• NM_020822.3:c.1637C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_020822.3(KCNT1):​c.1637C>T​(p.Pro546Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000302 in 1,454,586 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 5.91

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_benign. Variant got -6 ACMG points.

• BP6: Variant 9-135770315-C-T is Benign according to our data. Variant chr9-135770315-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 473361.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNT1	NM_020822.3	c.1637C>T	p.Pro546Leu	missense_variant	Exon 17 of 31	ENST00000371757.7	NP_065873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7	c.1637C>T	p.Pro546Leu	missense_variant	Exon 17 of 31	1	NM_020822.3	ENSP00000360822.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000328 AC: 8 AN: 244246 Hom.: 0 AF XY: 0.0000302 AC XY: 4 AN XY: 132416

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000275

Gnomad SAS exome AF: 0.0000338

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000302 AC: 44 AN: 1454586 Hom.: 0 Cov.: 31 AF XY: 0.0000277 AC XY: 20 AN XY: 723096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000343

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 25, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Found in a 16 year-old male who presented with a seizure and then was found to be in atrial fibrillation. Testing was done at Invitae. p.Pro546Leu (c.1637C>T) in exon 17 of the KCNT1 gene (NM_020822.2) Chromosome position: 9:138662161 C / T Based on the information reviewed below, we classify this as a Variant of Unknown Significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has not previously been reported in the literature in association with disease. It had not been reported to ClinVar as of 4/25/2017. This is a conservative amino acid change, resulting in the replacement of a nonpolar Proline with a nonpolar Leucine. Proline at this location is absolutely conserved across ~100 vertebrate species for which we have data. The adjacent residues are also highly conserved. However, there is no clearly Likely Pathogenic or Pathogenic missense variant currently listed in ClinVar at a nearby residue (+/- 10), which may indicate that this part of the protein is tolerant of change. According to the Invitae report, in silico algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been reported in 7 individuals in the gnomAD database, which includes variant calls on ~120,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 4/8,549 East Asians (for the highest allele frequency: 0.023%), 1/14,889 South Asians, and 2/54,072 non-Finnish Europeans. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -

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

Sep 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	.;.;.;.;.;.;.;.;T;.
Eigen	Benign	0.051
Eigen_PC	Benign	0.067
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	.;.;.;.;.;.;.;.;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.6	.;.;D;D;.;.;.;.;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.018	.;.;D;D;.;.;.;.;D;D
Sift4G	Uncertain	0.017	D;D;D;D;D;D;D;D;D;D
Polyphen		0.069	.;.;.;.;.;.;.;.;B;.
Vest4		0.87
MutPred		0.56		.;.;.;.;.;.;Loss of glycosylation at P527 (P = 0.0163);Loss of glycosylation at P527 (P = 0.0163);Loss of glycosylation at P527 (P = 0.0163);Loss of glycosylation at P527 (P = 0.0163);
MVP		0.67
MPC		0.71
ClinPred		0.26	T
GERP RS		4.2
Varity_R		0.36
gMVP		0.78

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: rs770986306; hg19: chr9-138662161;