8-132480483-TCGCCGCCGC-TCGCCGCCGCCGCCGC

Variant names:

• chr8-132480483-T-TCGCCGC
• rs981093917
• NM_004519.4:c.44_49dupGCGGCG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_004519.4(KCNQ3):​c.44_49dupGCGGCG​(p.Gly15_Gly16dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000047 in 1,063,240 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000047 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.552
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_004519.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ3	NM_004519.4	c.44_49dupGCGGCG	p.Gly15_Gly16dup	conservative_inframe_insertion	Exon 1 of 15	ENST00000388996.10	NP_004510.1
KCNQ3	XM_047421769.1	c.44_49dupGCGGCG	p.Gly15_Gly16dup	conservative_inframe_insertion	Exon 1 of 15		XP_047277725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10	c.44_49dupGCGGCG	p.Gly15_Gly16dup	conservative_inframe_insertion	Exon 1 of 15	1	NM_004519.4	ENSP00000373648.3
KCNQ3	ENST00000519445.5	c.44_49dupGCGGCG	p.Gly15_Gly16dup	conservative_inframe_insertion	Exon 1 of 15	5		ENSP00000428790.1
KCNQ3	ENST00000519589.1	n.-179_-174dupGCGGCG		upstream_gene_variant		2
KCNQ3	ENST00000639358.1	n.-182_-177dupGCGGCG		upstream_gene_variant		5		ENSP00000492691.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000470 AC: 5 AN: 1063240 Hom.: 0 Cov.: 31 AF XY: 0.00000590 AC XY: 3 AN XY: 508208

African (AFR) AF: 0.00 AC: 0 AN: 21516

American (AMR) AF: 0.00 AC: 0 AN: 7442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12476

East Asian (EAS) AF: 0.00 AC: 0 AN: 23278

South Asian (SAS) AF: 0.00 AC: 0 AN: 20818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2834

European-Non Finnish (NFE) AF: 0.00000547 AC: 5 AN: 913268

Other (OTH) AF: 0.00 AC: 0 AN: 41462

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 17, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.44_49dupGCGGCG variant (also known as p.G15_G16dup), located in coding exon 1 of the KCNQ3 gene, results from an in-frame duplication of GCGGCG at nucleotide positions 44 to 49. This results in the duplication of 2 extra residues (GG) between codons 15 and 16. These amino acid positions are not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Benign neonatal seizures Uncertain:1

Jan 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with KCNQ3-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.44_49dup, results in the insertion of 2 amino acid(s) of the KCNQ3 protein (p.Gly15_Gly16dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.55

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs981093917; hg19: chr8-133492730;