9-135702317-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020822.3(KCNT1):c.59G>C(p.Gly20Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00787 in 1,610,946 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G20R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0052 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0081 ( 84 hom. )

Consequence

KCNT1
NM_020822.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.571

Variant links:

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]

KCNT1 links:

SOHLH1 (HGNC:27845): (spermatogenesis and oogenesis specific basic helix-loop-helix 1) This gene encodes one of testis-specific transcription factors which are essential for spermatogenesis, oogenesis and folliculogenesis. This gene is located on chromosome 9. Mutations in this gene are associated with nonobstructive azoospermia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2013]

SOHLH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032934844).

BP6

Variant 9-135702317-G-C is Benign according to our data. Variant chr9-135702317-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 129366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135702317-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0052 (792/152174) while in subpopulation SAS AF= 0.0162 (78/4826). AF 95% confidence interval is 0.0133. There are 5 homozygotes in gnomad4. There are 392 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 792 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNT1	NM_020822.3 link	c.59G>C	p.Gly20Ala	missense_variant	Exon 1 of 31	ENST00000371757.7	NP_065873.2	Q5JUK3-3
KCNT1	NM_001272003.2 link	c.59G>C	p.Gly20Ala	missense_variant	Exon 1 of 31		NP_001258932.1	Q5JUK3-4
SOHLH1	XM_011518698.4 link	c.-2213C>G		upstream_gene_variant			XP_011517000.1
SOHLH1	XM_006717109.5 link	c.-2342C>G		upstream_gene_variant			XP_006717172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7 link	c.59G>C	p.Gly20Ala	missense_variant	Exon 1 of 31	1	NM_020822.3	ENSP00000360822.2		Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.00522

AC:

794

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00464

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.00369

Gnomad SAS

AF:

0.0161

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00718

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00663

AC:

1603

AN:

241640

Hom.:

AF XY:

0.00758

AC XY:

1003

AN XY:

132366

show subpopulations

Gnomad AFR exome

AF:

0.00120

Gnomad AMR exome

AF:

0.00367

Gnomad ASJ exome

AF:

0.0153

Gnomad EAS exome

AF:

0.000952

Gnomad SAS exome

AF:

0.0150

Gnomad FIN exome

AF:

0.000420

Gnomad NFE exome

AF:

0.00731

Gnomad OTH exome

AF:

0.00761

GnomAD4 exome

AF:

0.00815

AC:

11886

AN:

1458772

Hom.:

Cov.:

AF XY:

0.00844

AC XY:

6124

AN XY:

725746

show subpopulations

Gnomad4 AFR exome

AF:

0.00168

Gnomad4 AMR exome

AF:

0.00358

Gnomad4 ASJ exome

AF:

0.0155

Gnomad4 EAS exome

AF:

0.0145

Gnomad4 SAS exome

AF:

0.0147

Gnomad4 FIN exome

AF:

0.000346

Gnomad4 NFE exome

AF:

0.00788

Gnomad4 OTH exome

AF:

0.00790

GnomAD4 genome

AF:

0.00520

AC:

792

AN:

152174

Hom.:

Cov.:

AF XY:

0.00527

AC XY:

392

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00464

Gnomad4 ASJ

AF:

0.0150

Gnomad4 EAS

AF:

0.00370

Gnomad4 SAS

AF:

0.0162

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00717

Gnomad4 OTH

AF:

0.00522

Alfa

AF:

0.00599

Hom.:

Bravo

AF:

0.00520

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00688

AC:

ExAC

AF:

0.00630

AC:

759

EpiCase

AF:

0.00763

EpiControl

AF:

0.00982

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Feb 08, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 22, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNT1: BS1, BS2 -

Jun 21, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

May 17, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Developmental and epileptic encephalopathy, 14

Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nocturnal frontal lobe epilepsy 5

Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.77

CADD

Benign

5.1

DANN

Benign

0.72

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.51

T;T;T

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Benign

-0.97

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.95

N;.;N

REVEL

Benign

0.048

Sift

Benign

0.33

T;.;T

Sift4G

Pathogenic

0.0

D;T;D

Vest4

0.15

MVP

0.030

MPC

0.68

ClinPred

0.0026

GERP RS

0.96

gMVP

0.088

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over