rs764544537

Positions:

• chr8-132129498-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004519.4(KCNQ3):​c.2383G>A​(p.Val795Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.65

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25231287).
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ3	NM_004519.4	c.2383G>A	p.Val795Ile	missense_variant	15/15	ENST00000388996.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ3	ENST00000388996.10	c.2383G>A	p.Val795Ile	missense_variant	15/15	1	NM_004519.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251304 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135820

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Benign neonatal seizures Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2021

This variant is present in population databases (rs764544537, ExAC 0.01%). This sequence change replaces valine with isoleucine at codon 795 of the KCNQ3 protein (p.Val795Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant has not been reported in the literature in individuals with a KCNQ3-related disease. ClinVar contains an entry for this variant (Variation ID: 205993). In summary, this variant has uncertain impact on KCNQ3 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 10, 2017

p.Val795Ile (GTC>ATC): c.2383 G>A in exon 15 of the KCNQ3 gene (NM_004519.2) The Val795Ile missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is conservative as both Valine and Isoleucine are uncharged, non-polar amino acid residues. However, Val795Ile alters a conserved position in the C-terminal region of the KCNQ3 protein and in silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Val795Ile is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	2.0	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.42	N;.;N;N;.
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D;.;D;D;.
Sift4G	Uncertain	0.024	D;D;D;D;.
Polyphen		0.73	P;.;.;P;.
Vest4		0.29
MutPred		0.34		Gain of sheet (P = 0.0221);.;.;.;.;
MVP		0.36
MPC		0.26
ClinPred		0.71	D
GERP RS		4.8
Varity_R		0.25
gMVP		0.30

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: rs764544537; hg19: chr8-133141745;