rs146152956

Positions:

chr9-135702357-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_020822.3(KCNT1):c.99A>G(p.Gln33=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 1,610,794 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 7 hom. )

Consequence

KCNT1
NM_020822.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -0.149

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 9-135702357-A-G is Benign according to our data. Variant chr9-135702357-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193439.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}. Variant chr9-135702357-A-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.149 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00314 (477/151724) while in subpopulation AFR AF= 0.00454 (188/41368). AF 95% confidence interval is 0.00401. There are 3 homozygotes in gnomad4. There are 226 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 477 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3 linkuse as main transcript	c.99A>G	p.Gln33=	synonymous_variant	1/31	ENST00000371757.7	NP_065873.2
KCNT1	NM_001272003.2 linkuse as main transcript	c.99A>G	p.Gln33=	synonymous_variant	1/31		NP_001258932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7 linkuse as main transcript	c.99A>G	p.Gln33=	synonymous_variant	1/31	1	NM_020822.3	ENSP00000360822	A2	Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.00313

AC:

475

AN:

151608

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00451

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00269

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00157

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.000379

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00312

Gnomad OTH

AF:

0.00385

GnomAD3 exomes

AF:

0.00209

AC:

513

AN:

244966

Hom.:

AF XY:

0.00208

AC XY:

278

AN XY:

133644

show subpopulations

Gnomad AFR exome

AF:

0.00407

Gnomad AMR exome

AF:

0.00160

Gnomad ASJ exome

AF:

0.00252

Gnomad EAS exome

AF:

0.000717

Gnomad SAS exome

AF:

0.000654

Gnomad FIN exome

AF:

0.000418

Gnomad NFE exome

AF:

0.00284

Gnomad OTH exome

AF:

0.00315

GnomAD4 exome

AF:

0.00257

AC:

3753

AN:

1459070

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

1853

AN XY:

725912

show subpopulations

Gnomad4 AFR exome

AF:

0.00559

Gnomad4 AMR exome

AF:

0.00175

Gnomad4 ASJ exome

AF:

0.00334

Gnomad4 EAS exome

AF:

0.00391

Gnomad4 SAS exome

AF:

0.000615

Gnomad4 FIN exome

AF:

0.000346

Gnomad4 NFE exome

AF:

0.00272

Gnomad4 OTH exome

AF:

0.00229

GnomAD4 genome

AF:

0.00314

AC:

477

AN:

151724

Hom.:

Cov.:

AF XY:

0.00305

AC XY:

226

AN XY:

74184

show subpopulations

Gnomad4 AFR

AF:

0.00454

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00157

Gnomad4 SAS

AF:

0.000625

Gnomad4 FIN

AF:

0.000379

Gnomad4 NFE

AF:

0.00312

Gnomad4 OTH

AF:

0.00381

Alfa

AF:

0.00288

Hom.:

Bravo

AF:

0.00344

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00382

EpiControl

AF:

0.00410

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	KCNT1: BP4, BP7, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2016

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

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.9

DANN

Benign

0.29

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