rs118192251

chr8-132174295-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004519.4(KCNQ3):c.988C>T(p.Arg330Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,399,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R330H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 4.65

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a topological_domain Extracellular (size 5) in uniprot entity KCNQ3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_004519.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-132174294-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 852086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 8-132174295-G-A is Pathogenic according to our data. Variant chr8-132174295-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132174295-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ3	NM_004519.4	c.988C>T	p.Arg330Cys	missense_variant	6/15	ENST00000388996.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ3	ENST00000388996.10	c.988C>T	p.Arg330Cys	missense_variant	6/15	1	NM_004519.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399984 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690562

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	literature only	GeneReviews	-	Same variant detected in 2 unrelated families -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 23146207, PS1). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.973, 3Cnet: 0.981, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Benign neonatal seizures Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 15, 2023

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ3 protein function. ClinVar contains an entry for this variant (Variation ID: 21417). This missense change has been observed in individuals with benign familial neonatal seizures (PMID: 18249525, 23146207). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 330 of the KCNQ3 protein (p.Arg330Cys). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2022

Published functional studies demonstrate abnormal channel function (Miceli et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23146207, 16883520, 28717674, 35627257, 34474328, 18249525, 25524373, 34136434) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.;.;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.7	D;.;D;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		1.0	D;.;.;D;.
Vest4		0.87
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.88
gMVP		0.98

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: rs118192251; hg19: chr8-133186542; COSMIC: COSV101196138;