rs118192251

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 4.65

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

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 Lovd as [Likely_pathogenic].

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 rank	MANE	Protein	UniProt
KCNQ3	NM_004519.4 link	c.988C>T	p.Arg330Cys	missense_variant	Exon 6 of 15	ENST00000388996.10	NP_004510.1	O43525-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10 link	c.988C>T	p.Arg330Cys	missense_variant	Exon 6 of 15	1	NM_004519.4	ENSP00000373648.3		O43525-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1399984

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690562

show subpopulations

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.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Seizures, benign familial neonatal, 2

Pathogenic:4Other:1

Oct 02, 2021

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Same variant detected in 2 unrelated families -

May 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 08, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Benign neonatal seizures

Pathogenic:1

May 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 05, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;.;.;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;.;.;.;.

PrimateAI

Pathogenic

0.89

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

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

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