8-132480484-C-T

Variant names:

• chr8-132480484-C-T
• rs1355500787
• NM_004519.4:c.49G>A

Variant summary

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

The NM_004519.4(KCNQ3):​c.49G>A​(p.Asp17Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000208 in 1,201,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.552

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=0.17443812).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ3	NM_004519.4	c.49G>A	p.Asp17Asn	missense_variant	Exon 1 of 15	ENST00000388996.10	NP_004510.1
KCNQ3	XM_047421769.1	c.49G>A	p.Asp17Asn	missense_variant	Exon 1 of 15		XP_047277725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10	c.49G>A	p.Asp17Asn	missense_variant	Exon 1 of 15	1	NM_004519.4	ENSP00000373648.3
KCNQ3	ENST00000519445.5	c.49G>A	p.Asp17Asn	missense_variant	Exon 1 of 15	5		ENSP00000428790.1
KCNQ3	ENST00000519589.1	n.-174G>A		upstream_gene_variant		2
KCNQ3	ENST00000639358.1	n.-177G>A		upstream_gene_variant		5		ENSP00000492691.1

Frequencies

GnomAD3 genomes AF: 0.0000334 AC: 5 AN: 149564 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000190 AC: 20 AN: 1051726 Hom.: 0 Cov.: 31 AF XY: 0.0000199 AC XY: 10 AN XY: 502370

Gnomad4 AFR exome AF: 0.0000473

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: 0.0000177

Gnomad4 OTH exome AF: 0.0000737

GnomAD4 genome AF: 0.0000334 AC: 5 AN: 149564 Hom.: 0 Cov.: 33 AF XY: 0.0000548 AC XY: 4 AN XY: 72948

Gnomad4 AFR AF: 0.0000974

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000149

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Benign neonatal seizures Uncertain:1

Nov 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 17 of the KCNQ3 protein (p.Asp17Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 538548). 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) performed at Invitae indicates that this missense variant is not expected to disrupt KCNQ3 protein function. 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	0.17
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.52	T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	0.0	N;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.54	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.067	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.050	B;B
Vest4		0.25
MutPred		0.21		Gain of MoRF binding (P = 0.0563);Gain of MoRF binding (P = 0.0563);
MVP		0.67
MPC		0.89
ClinPred		0.095	T
GERP RS		2.8
Varity_R		0.084
gMVP		0.20

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: rs1355500787; hg19: chr8-133492731;