NM_004519.4:c.386+13229C>A

Variant names:

• chr8-132466918-G-T
• rs2673559
• NM_004519.4:c.386+13229C>A

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+13229C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 152,058 control chromosomes in the GnomAD database, including 42,361 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 0.74 (42361 hom., cov: 31)
• Consequence: KCNQ3 NM_004519.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.39
• Publications: 4 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ3	NM_004519.4	c.386+13229C>A		intron_variant	Intron 1 of 14	ENST00000388996.10	NP_004510.1
KCNQ3	XM_047421769.1	c.386+13229C>A		intron_variant	Intron 1 of 14		XP_047277725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10	c.386+13229C>A		intron_variant	Intron 1 of 14	1	NM_004519.4	ENSP00000373648.3
KCNQ3	ENST00000519445.5	c.386+13229C>A		intron_variant	Intron 1 of 14	5		ENSP00000428790.1
KCNQ3	ENST00000519589.1	n.164+13229C>A		intron_variant	Intron 1 of 13	2
KCNQ3	ENST00000639358.1	n.161+13229C>A		intron_variant	Intron 1 of 6	5		ENSP00000492691.1

Frequencies

GnomAD3 genomes AF: 0.744 AC: 112979 AN: 151940 Hom.: 42325 Cov.: 31

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.674

Gnomad ASJ AF: 0.774

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.714

Gnomad FIN AF: 0.759

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.736

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

GnomAD4 genome AF: 0.744 AC: 113071 AN: 152058 Hom.: 42361 Cov.: 31 AF XY: 0.743 AC XY: 55198 AN XY: 74322

African (AFR) AF: 0.807 AC: 33501 AN: 41490

American (AMR) AF: 0.674 AC: 10286 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.774 AC: 2686 AN: 3470

East Asian (EAS) AF: 0.539 AC: 2768 AN: 5138

South Asian (SAS) AF: 0.715 AC: 3442 AN: 4816

European-Finnish (FIN) AF: 0.759 AC: 8034 AN: 10586

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.736 AC: 50051 AN: 67976

Other (OTH) AF: 0.736 AC: 1554 AN: 2112

Alfa AF: 0.734 Hom.: 53774

Bravo AF: 0.733

Asia WGS AF: 0.641 AC: 2232 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0010
DANN	Benign	0.73
PhyloP100		-2.4
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: rs2673559; hg19: chr8-133479165;