rs148162797

chr9-135772926-C-Gchr9-135772926-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020822.3(KCNT1):c.2220C>G(p.Asp740Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,518,882 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D740D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (10 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -4.50

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068859756).
• BP6: Variant 9-135772926-C-G is Benign according to our data. Variant chr9-135772926-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 473370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135772926-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000302 (46/152300) while in subpopulation SAS AF= 0.00456 (22/4822). AF 95% confidence interval is 0.00309. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.2220C>G	p.Asp740Glu	missense_variant	19/31	ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.2220C>G	p.Asp740Glu	missense_variant	19/31	1	NM_020822.3	A2

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000737 AC: 93 AN: 126108 Hom.: 1 AF XY: 0.000901 AC XY: 61 AN XY: 67692

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000417

Gnomad ASJ exome AF: 0.000344

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00396

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000252

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000334 AC: 456 AN: 1366582 Hom.: 10 Cov.: 31 AF XY: 0.000451 AC XY: 303 AN XY: 672564

Gnomad4 AFR exome AF: 0.0000324

Gnomad4 AMR exome AF: 0.000326

Gnomad4 ASJ exome AF: 0.000305

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00415

Gnomad4 FIN exome AF: 0.000209

Gnomad4 NFE exome AF: 0.0000768

Gnomad4 OTH exome AF: 0.000477

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.000484 AC XY: 36 AN XY: 74452

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000254 Hom.: 0

Bravo AF: 0.000204

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000530 AC: 62

ClinVar

Significance: Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	KCNT1: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2019	This variant is associated with the following publications: (PMID: 31780880) -

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 24, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 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. -

KCNT1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 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). -

Developmental and epileptic encephalopathy, 14 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Autosomal dominant nocturnal frontal lobe epilepsy 5 Benign:1

Likely 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	Benign	0.079
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.0020
Dann	Benign	0.47
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.72	T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0069	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.91	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
REVEL	Benign	0.22
Sift4G	Benign	0.50	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0030	.;.;.;.;.;.;.;.;B;.
Vest4		0.27
MutPred		0.41		.;.;.;.;.;.;Gain of solvent accessibility (P = 0.0155);Gain of solvent accessibility (P = 0.0155);Gain of solvent accessibility (P = 0.0155);.;
MVP		0.66
MPC		0.59
ClinPred		0.012	T
GERP RS		-7.8
Varity_R		0.033
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs148162797; hg19: chr9-138664772;