rs74582884

chr8-132134369-G-Achr8-132134369-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004519.4(KCNQ3):c.1720C>T(p.Pro574Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,612,916 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts 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. P574T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (9 hom.)
• Consequence: KCNQ3 NM_004519.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 9.32

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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, phyloP100way_vertebrate, REVEL [when AlphaMissense, FATHMM_MKL, MetaRNN, MutationTaster, PROVEAN was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.01873827).
• BP6: Variant 8-132134369-G-A is Benign according to our data. Variant chr8-132134369-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 21411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132134369-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00246 (374/152208) while in subpopulation AMR AF= 0.0053 (81/15282). AF 95% confidence interval is 0.00437. There are 4 homozygotes in gnomad4. There are 188 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 374 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ3	NM_004519.4	c.1720C>T	p.Pro574Ser	missense_variant	13/15	ENST00000388996.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ3	ENST00000388996.10	c.1720C>T	p.Pro574Ser	missense_variant	13/15	1	NM_004519.4	P1

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 374 AN: 152090 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00531

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00366

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00212 AC: 534 AN: 251432 Hom.: 1 AF XY: 0.00206 AC XY: 280 AN XY: 135884

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00346

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00277 AC: 4049 AN: 1460708 Hom.: 9 Cov.: 30 AF XY: 0.00274 AC XY: 1990 AN XY: 726748

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00332

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.00246 AC: 374 AN: 152208 Hom.: 4 Cov.: 31 AF XY: 0.00253 AC XY: 188 AN XY: 74412

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00530

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00366

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00345 Hom.: 1

Bravo AF: 0.00250

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00199 AC: 242

EpiCase AF: 0.00393

EpiControl AF: 0.00397

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	KCNQ3: PM5, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2018	Published functional studies demonstrate no damaging effect, specifically, voltage clamp analysis revealed no significant reduction in potassium current as compared to wildtype (Neubauer et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28351718, 20981092, 18625963, 19344764, 23596459, 25784856, 28488083, 27875746, 29948376) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Seizures, benign familial neonatal, 2 Benign:4 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Allele is present at 0.3% in non-Finnish Europeans and 0.2% in Latinos (gnomAD). Overrepresented (p=0.008) in idiopathic generalized epilepsies (8/455 persons). Detected in other complex phenotypes; in 4 persons with rolandic epilepsy and in 1 with rolandic epilepsy and moderate psychomotor delay; in 3 persons with autism spectrum disorders and no additional neurologic features -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 31, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 03, 2014	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 2018

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. -

Benign Neonatal Epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Benign neonatal seizures Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Intellectual disability Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Apr 20, 2020

- -

KCNQ3-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 2019

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	0.31
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D;.;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.019	T;T;T;T;T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.1	M;.;.;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	N;.;N;N;.
REVEL	Pathogenic	0.83
Sift	Benign	0.11	T;.;T;T;.
Sift4G	Benign	0.092	T;T;T;T;.
Polyphen		1.0	D;.;.;D;.
Vest4		0.67
MVP		0.89
MPC		0.51
ClinPred		0.037	T
GERP RS		5.5
Varity_R		0.17
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs74582884; hg19: chr8-133146616;