8-132356847-C-G

Variant names:

• chr8-132356847-C-G
• rs978152
• NM_004519.4:c.386+123300G>C

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+123300G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 151,914 control chromosomes in the GnomAD database, including 19,528 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 0.47 (19528 hom., cov: 32)
• Consequence: KCNQ3 NM_004519.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.306
• Publications: 10 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):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• seizures, benign familial neonatal, 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• self-limited familial neonatal epilepsy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004519.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	NM_004519.4	MANE Select	c.386+123300G>C		intron	N/A	NP_004510.1	O43525-1
	KCNQ3	NM_001204824.2		c.26+90354G>C		intron	N/A	NP_001191753.1	O43525-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	ENST00000388996.10	TSL:1 MANE Select	c.386+123300G>C		intron	N/A	ENSP00000373648.3	O43525-1
	KCNQ3	ENST00000519445.5	TSL:5	c.386+123300G>C		intron	N/A	ENSP00000428790.1	E7ET42
	KCNQ3	ENST00000521134.6	TSL:2	c.26+90354G>C		intron	N/A	ENSP00000429799.1	O43525-2

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71595 AN: 151798 Hom.: 19507 Cov.: 32

Gnomad AFR AF: 0.761

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.444

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

GnomAD4 genome AF: 0.472 AC: 71647 AN: 151914 Hom.: 19528 Cov.: 32 AF XY: 0.469 AC XY: 34822 AN XY: 74220

African (AFR) AF: 0.761 AC: 31552 AN: 41460

American (AMR) AF: 0.436 AC: 6652 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1435 AN: 3470

East Asian (EAS) AF: 0.432 AC: 2230 AN: 5166

South Asian (SAS) AF: 0.339 AC: 1634 AN: 4818

European-Finnish (FIN) AF: 0.355 AC: 3734 AN: 10506

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.340 AC: 23100 AN: 67926

Other (OTH) AF: 0.444 AC: 937 AN: 2112

Alfa AF: 0.235 Hom.: 492

Bravo AF: 0.493

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.9
DANN	Benign	0.69
PhyloP100		0.31
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: rs978152; hg19: chr8-133369094;