rs141281093

chr9-135771015-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_020822.3(KCNT1):c.1928G>A(p.Arg643Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,613,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. R643W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.94

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0140633285).
• BP6: Variant 9-135771015-G-A is Benign according to our data. Variant chr9-135771015-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 386260.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=3, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.1928G>A	p.Arg643Gln	missense_variant	18/31	ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.1928G>A	p.Arg643Gln	missense_variant	18/31	1	NM_020822.3	A2

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000233 AC: 58 AN: 248562 Hom.: 0 AF XY: 0.000200 AC XY: 27 AN XY: 134804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00180

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000276

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000170 AC: 248 AN: 1461346 Hom.: 0 Cov.: 33 AF XY: 0.000172 AC XY: 125 AN XY: 726934

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000149

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74476

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000363 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000297 AC: 36

EpiCase AF: 0.000218

EpiControl AF: 0.000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	KCNT1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2021	This variant is associated with the following publications: (PMID: 28166811) -

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 30, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	14
Dann	Benign	0.32
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.014	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.97	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
REVEL	Benign	0.053
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;.;.;.;.;B;.
Vest4		0.16
MVP		0.32
MPC		0.73
ClinPred		0.013	T
GERP RS		0.17
Varity_R		0.026
gMVP		0.20

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: rs141281093; hg19: chr9-138662861;