8-132170370-C-T

Variant names:

• chr8-132170370-C-T
• rs943073757
• NM_004519.4:c.1199G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004519.4(KCNQ3):​c.1199G>A​(p.Arg400Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.11

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ3	NM_004519.4	c.1199G>A	p.Arg400Lys	missense_variant	Exon 8 of 15	ENST00000388996.10	NP_004510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10	c.1199G>A	p.Arg400Lys	missense_variant	Exon 8 of 15	1	NM_004519.4	ENSP00000373648.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461712 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727144

Gnomad4 AFR exome AF: 0.0000896

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Seizures, benign familial neonatal, 2 Uncertain:2

Nov 07, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Dec 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KCNQ3-related disorder Uncertain:1

Sep 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KCNQ3 c.1199G>A variant is predicted to result in the amino acid substitution p.Arg400Lys. To our knowledge, this variant has not been reported in the literature. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Benign neonatal seizures Uncertain:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 400 of the KCNQ3 protein (p.Arg400Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNQ3-related conditions. ClinVar contains an entry for this variant (Variation ID: 471214). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KCNQ3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.22	T;.;.;.;.
Eigen	Benign	-0.051
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	T;T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Uncertain	0.73	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.50	N;.;N;N;.
REVEL	Uncertain	0.55
Sift	Benign	1.0	T;.;T;T;.
Sift4G	Benign	1.0	T;T;T;T;.
Polyphen		0.82	P;.;.;P;.
Vest4		0.39
MutPred		0.53		Gain of ubiquitination at R400 (P = 0.0114);.;.;Gain of ubiquitination at R400 (P = 0.0114);.;
MVP		0.91
MPC		1.0
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.59
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs943073757; hg19: chr8-133182617;