8-132172667-G-C

Position:

chr8-132172667-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004519.4(KCNQ3):c.1071C>G(p.Leu357Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 1,613,580 control chromosomes in the GnomAD database, including 3,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.051 ( 315 hom., cov: 33)

Exomes 𝑓: 0.064 ( 3356 hom. )

Consequence

KCNQ3
NM_004519.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.194

Variant links:

Genes affected

KCNQ3 (HGNC:6297): (potassium voltage-gated channel subfamily Q member 3) This gene encodes a protein that functions in the regulation of neuronal excitability. The encoded protein forms an M-channel by associating with the products of the related KCNQ2 or KCNQ5 genes, which both encode integral membrane proteins. M-channel currents are inhibited by M1 muscarinic acetylcholine receptors and are activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 2 (BFNC2), also known as epilepsy, benign neonatal type 2 (EBN2). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

KCNQ3 links:

KCNQ3 (HGNC:):

KCNQ3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 8-132172667-G-C is Benign according to our data. Variant chr8-132172667-G-C is described in ClinVar as [Benign]. Clinvar id is 129347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132172667-G-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.194 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ3	NM_004519.4 linkuse as main transcript	c.1071C>G	p.Leu357Leu	synonymous_variant	7/15	ENST00000388996.10	NP_004510.1	O43525-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10 linkuse as main transcript	c.1071C>G	p.Leu357Leu	synonymous_variant	7/15	1	NM_004519.4	ENSP00000373648.3		O43525-1

Frequencies

GnomAD3 genomes

AF:

0.0512

AC:

7784

AN:

152180

Hom.:

315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0153

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0297

Gnomad ASJ

AF:

0.0357

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0130

Gnomad FIN

AF:

0.124

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0738

Gnomad OTH

AF:

0.0455

GnomAD3 exomes

AF:

0.0523

AC:

13119

AN:

250804

Hom.:

537

AF XY:

0.0529

AC XY:

7176

AN XY:

135588

show subpopulations

Gnomad AFR exome

AF:

0.0126

Gnomad AMR exome

AF:

0.0233

Gnomad ASJ exome

AF:

0.0413

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0149

Gnomad FIN exome

AF:

0.124

Gnomad NFE exome

AF:

0.0729

Gnomad OTH exome

AF:

0.0534

GnomAD4 exome

AF:

0.0645

AC:

94228

AN:

1461282

Hom.:

3356

Cov.:

AF XY:

0.0632

AC XY:

45961

AN XY:

726970

show subpopulations

Gnomad4 AFR exome

AF:

0.0125

Gnomad4 AMR exome

AF:

0.0245

Gnomad4 ASJ exome

AF:

0.0398

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0163

Gnomad4 FIN exome

AF:

0.121

Gnomad4 NFE exome

AF:

0.0721

Gnomad4 OTH exome

AF:

0.0571

GnomAD4 genome

AF:

0.0511

AC:

7781

AN:

152298

Hom.:

315

Cov.:

AF XY:

0.0517

AC XY:

3849

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0152

Gnomad4 AMR

AF:

0.0297

Gnomad4 ASJ

AF:

0.0357

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.0128

Gnomad4 FIN

AF:

0.124

Gnomad4 NFE

AF:

0.0738

Gnomad4 OTH

AF:

0.0450

Alfa

AF:

0.0507

Hom.:

Bravo

AF:

0.0435

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.0673

EpiControl

AF:

0.0660

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Benign neonatal seizures

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

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. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 2016

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. -

Seizures, benign familial neonatal, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

5.9

DANN

Benign

0.80

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