rs151272083

chr9-135778822-G-Achr9-135778822-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PP3_Strong BP6 BS1 BS2

The NM_020822.3(KCNT1):c.2729G>A(p.Arg910Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000701 in 1,608,188 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R910W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (1 hom.)
• Consequence: KCNT1 NM_020822.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 7.70

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 -5 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 9-135778822-G-A is Benign according to our data. Variant chr9-135778822-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224109.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=7, Benign=4}. Variant chr9-135778822-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00154 (234/152210) while in subpopulation NFE AF= 0.00253 (172/67998). AF 95% confidence interval is 0.00222. There are 1 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 234 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.2729G>A	p.Arg910Gln	missense_variant, splice_region_variant	23/31	ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.2729G>A	p.Arg910Gln	missense_variant, splice_region_variant	23/31	1	NM_020822.3	A2

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152092 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000456 AC: 114 AN: 249824 Hom.: 0 AF XY: 0.000355 AC XY: 48 AN XY: 135260

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.000403

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000835

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000613 AC: 893 AN: 1455978 Hom.: 1 Cov.: 33 AF XY: 0.000639 AC XY: 463 AN XY: 724444

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00196

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000565

Gnomad4 NFE exome AF: 0.000678

Gnomad4 OTH exome AF: 0.000864

GnomAD4 genome AF: 0.00154 AC: 234 AN: 152210 Hom.: 1 Cov.: 33 AF XY: 0.00140 AC XY: 104 AN XY: 74410

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00253

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.00220 Hom.: 0

Bravo AF: 0.00152

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00138 AC: 168

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2020	This variant is associated with the following publications: (PMID: 26105150, 28554332) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	KCNT1: BS1 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 12, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Developmental and epileptic encephalopathy, 14 Benign:3

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	- -
Likely benign, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Apr 16, 2018	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	KCNT1 NM_020822 exon 23 p.Arg910Gln (c.2729G>A): This variant has not been reported in the literature but is present in 109/125624 European individuals in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs151272083). This variant is present in ClinVar (Variation ID:224109). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 15, 2016

- -

KCNT1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2018

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	0.92
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	35
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.34	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
REVEL	Uncertain	0.53
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;.;.;.;D;.
Vest4		0.67
MVP		0.87
MPC		1.7
ClinPred		0.46	T
GERP RS		4.4
Varity_R		0.57
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.48		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs151272083; hg19: chr9-138670668;