NM_004519.4:c.386+80787G>T

Variant names:

• chr8-132399360-C-A
• rs2673604
• NM_004519.4:c.386+80787G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004519.4(KCNQ3):​c.386+80787G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 151,922 control chromosomes in the GnomAD database, including 30,553 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.62 (30553 hom., cov: 31)
• Consequence: KCNQ3 NM_004519.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0780
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• seizures, benign familial neonatal, 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign neonatal seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ3	NM_004519.4	c.386+80787G>T		intron_variant	Intron 1 of 14	ENST00000388996.10	NP_004510.1
KCNQ3	NM_001204824.2	c.26+47841G>T		intron_variant	Intron 1 of 14		NP_001191753.1
KCNQ3	XM_047421769.1	c.386+80787G>T		intron_variant	Intron 1 of 14		XP_047277725.1
KCNQ3	XM_011517026.3	c.26+31103G>T		intron_variant	Intron 1 of 14		XP_011515328.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10	c.386+80787G>T		intron_variant	Intron 1 of 14	1	NM_004519.4	ENSP00000373648.3

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94661 AN: 151808 Hom.: 30529 Cov.: 31

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.790

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.734

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.708

Gnomad OTH AF: 0.636

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.624 AC: 94725 AN: 151922 Hom.: 30553 Cov.: 31 AF XY: 0.622 AC XY: 46179 AN XY: 74224

African (AFR) AF: 0.464 AC: 19239 AN: 41420

American (AMR) AF: 0.606 AC: 9256 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 2329 AN: 3470

East Asian (EAS) AF: 0.577 AC: 2961 AN: 5136

South Asian (SAS) AF: 0.734 AC: 3522 AN: 4798

European-Finnish (FIN) AF: 0.670 AC: 7089 AN: 10574

Middle Eastern (MID) AF: 0.651 AC: 190 AN: 292

European-Non Finnish (NFE) AF: 0.708 AC: 48085 AN: 67936

Other (OTH) AF: 0.635 AC: 1337 AN: 2106

Alfa AF: 0.669 Hom.: 16940

Bravo AF: 0.606

Asia WGS AF: 0.689 AC: 2397 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.5
DANN	Benign	0.80
PhyloP100		-0.078
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2673604; hg19: chr8-133411607;