rs149804567

chr9-135778444-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020822.3(KCNT1):c.2543A>G(p.Glu848Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,552,002 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (9 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 9.00

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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.021965742).
• BP6: Variant 9-135778444-A-G is Benign according to our data. Variant chr9-135778444-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 129358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135778444-A-G is described in Lovd as [Likely_benign]. Variant chr9-135778444-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00231 (352/152290) while in subpopulation AMR AF= 0.00444 (68/15312). AF 95% confidence interval is 0.00359. There are 1 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 352 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.2543A>G	p.Glu848Gly	missense_variant	22/31	ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.2543A>G	p.Glu848Gly	missense_variant	22/31	1	NM_020822.3	A2

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 352 AN: 152172 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00346

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00229 AC: 361 AN: 157314 Hom.: 1 AF XY: 0.00226 AC XY: 187 AN XY: 82848

Gnomad AFR exome AF: 0.000340

Gnomad AMR exome AF: 0.00391

Gnomad ASJ exome AF: 0.000352

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000741

Gnomad FIN exome AF: 0.00145

Gnomad NFE exome AF: 0.00329

Gnomad OTH exome AF: 0.00405

GnomAD4 exome AF: 0.00300 AC: 4200 AN: 1399712 Hom.: 9 Cov.: 32 AF XY: 0.00287 AC XY: 1981 AN XY: 690470

Gnomad4 AFR exome AF: 0.000632

Gnomad4 AMR exome AF: 0.00408

Gnomad4 ASJ exome AF: 0.000159

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000844

Gnomad4 FIN exome AF: 0.000798

Gnomad4 NFE exome AF: 0.00343

Gnomad4 OTH exome AF: 0.00314

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152290 Hom.: 1 Cov.: 33 AF XY: 0.00244 AC XY: 182 AN XY: 74468

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00444

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00103

Gnomad4 NFE AF: 0.00346

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00297 Hom.: 3

Bravo AF: 0.00235

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000942 AC: 4

ESP6500EA AF: 0.00288 AC: 24

ExAC AF: 0.000843 AC: 86

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 15, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	KCNT1: BS1 -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 20, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 15, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Developmental and epileptic encephalopathy, 14 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 20, 2019

This alteration is classified as likely 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. -

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
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.022	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.067	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.3	D;.;D;.;.;.;.;.;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;.;D;.;.;.;.;.;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D
Polyphen		0.86	.;.;.;.;.;.;.;.;P;.
Vest4		0.69
MVP		0.86
MPC		1.1
ClinPred		0.029	T
GERP RS		4.7
Varity_R		0.48
gMVP		0.94

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: rs149804567; hg19: chr9-138670290;