rs147551342

chr9-135755151-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020822.3(KCNT1):c.522G>A(p.Met174Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,612,268 control chromosomes in the GnomAD database, including 4 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (4 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.343

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01074186).
• BP6: Variant 9-135755151-G-A is Benign according to our data. Variant chr9-135755151-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241304.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=2}. Variant chr9-135755151-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000361 (55/152298) while in subpopulation AMR AF= 0.00105 (16/15292). AF 95% confidence interval is 0.000656. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.522G>A	p.Met174Ile	missense_variant	6/31	ENST00000371757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.522G>A	p.Met174Ile	missense_variant	6/31	1	NM_020822.3	A2

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000393 AC: 98 AN: 249278 Hom.: 0 AF XY: 0.000401 AC XY: 54 AN XY: 134798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000462

Gnomad OTH exome AF: 0.000991

GnomAD4 exome AF: 0.000384 AC: 561 AN: 1459970 Hom.: 4 Cov.: 30 AF XY: 0.000388 AC XY: 282 AN XY: 726328

Gnomad4 AFR exome AF: 0.000838

Gnomad4 AMR exome AF: 0.00146

Gnomad4 ASJ exome AF: 0.0000768

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000335

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74468

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000517 Hom.: 1

Bravo AF: 0.000638

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000655

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	KCNT1: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 11, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 12, 2017

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. -

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 27, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 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. -

KCNT1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	22
Dann	Benign	0.92
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.85	T;D;T;T;D;T;D;D;D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.46	T
REVEL	Benign	0.045
Sift4G	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T
Vest4		0.16
MutPred		0.47		.;.;.;.;.;.;Loss of catalytic residue at V137 (P = 0.0116);.;.;.;.;
MVP		0.29
MPC		0.71
ClinPred		0.0095	T
GERP RS		3.1
Varity_R		0.20
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs147551342; hg19: chr9-138646997;