rs77912754

chr9-135786409-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020822.3(KCNT1):c.3390G>A(p.Ala1130=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,580,114 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: KCNT1 NM_020822.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.45

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 9-135786409-G-A is Benign according to our data. Variant chr9-135786409-G-A is described in ClinVar as [Benign]. Clinvar id is 129365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135786409-G-A is described in Lovd as [Likely_benign]. Variant chr9-135786409-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00167 (255/152322) while in subpopulation EAS AF= 0.0279 (144/5170). AF 95% confidence interval is 0.0241. There are 7 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 255 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.3390G>A	p.Ala1130=	synonymous_variant	29/31	ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.3390G>A	p.Ala1130=	synonymous_variant	29/31	1	NM_020822.3	A2

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 255 AN: 152206 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0278

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00217 AC: 395 AN: 182256 Hom.: 3 AF XY: 0.00197 AC XY: 199 AN XY: 100766

Gnomad AFR exome AF: 0.00269

Gnomad AMR exome AF: 0.000513

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0244

Gnomad SAS exome AF: 0.000380

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000273

Gnomad OTH exome AF: 0.00124

GnomAD4 exome AF: 0.00107 AC: 1532 AN: 1427792 Hom.: 23 Cov.: 36 AF XY: 0.00106 AC XY: 750 AN XY: 707556

Gnomad4 AFR exome AF: 0.00220

Gnomad4 AMR exome AF: 0.000495

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0348

Gnomad4 SAS exome AF: 0.000266

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000219

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00167 AC: 255 AN: 152322 Hom.: 7 Cov.: 33 AF XY: 0.00177 AC XY: 132 AN XY: 74490

Gnomad4 AFR AF: 0.00228

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0279

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000381 Hom.: 0

Bravo AF: 0.00197

Asia WGS AF: 0.0120 AC: 41 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Developmental and epileptic encephalopathy, 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

Autosomal dominant nocturnal frontal lobe epilepsy 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.8
Dann	Benign	0.72

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: rs77912754; hg19: chr9-138678255;