8-132180202-A-G

Position:

• chr8-132180202-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000388996.10(KCNQ3):​c.732T>C​(p.Gly244=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0633 in 1,614,002 control chromosomes in the GnomAD database, including 3,673 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: 32)
  • Exomes 𝑓: 0.065 (3358 hom.)
• Consequence: KCNQ3 ENST00000388996.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.19

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 8-132180202-A-G is Benign according to our data. Variant chr8-132180202-A-G is described in ClinVar as [Benign]. Clinvar id is 129350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132180202-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ3	NM_004519.4	c.732T>C	p.Gly244=	synonymous_variant	4/15	ENST00000388996.10	NP_004510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10	c.732T>C	p.Gly244=	synonymous_variant	4/15	1	NM_004519.4	ENSP00000373648	P1

Frequencies

GnomAD3 genomes AF: 0.0513 AC: 7798 AN: 152096 Hom.: 315 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.0358

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0739

Gnomad OTH AF: 0.0459

GnomAD3 exomes AF: 0.0525 AC: 13178 AN: 251206 Hom.: 541 AF XY: 0.0530 AC XY: 7198 AN XY: 135786

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.0233

Gnomad ASJ exome AF: 0.0412

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0149

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.0730

Gnomad OTH exome AF: 0.0533

GnomAD4 exome AF: 0.0646 AC: 94421 AN: 1461788 Hom.: 3358 Cov.: 32 AF XY: 0.0633 AC XY: 46037 AN XY: 727200

Gnomad4 AFR exome AF: 0.0126

Gnomad4 AMR exome AF: 0.0246

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: 0.0722

Gnomad4 OTH exome AF: 0.0571

GnomAD4 genome AF: 0.0512 AC: 7795 AN: 152214 Hom.: 315 Cov.: 32 AF XY: 0.0518 AC XY: 3857 AN XY: 74400

Gnomad4 AFR AF: 0.0153

Gnomad4 AMR AF: 0.0297

Gnomad4 ASJ AF: 0.0358

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.0129

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.0740

Gnomad4 OTH AF: 0.0455

Alfa AF: 0.0599 Hom.: 151

Bravo AF: 0.0435

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0674

EpiControl AF: 0.0661

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	-	- -

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 12, 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	-0.72
CADD	Benign	0.94
DANN	Benign	0.57

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: rs41272387; hg19: chr8-133192449;