chr8-132480483-T-TCGC

Position:

• chr8-132480483-T-TCGC

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5 BS2

The NM_004519.4(KCNQ3):​c.47_49dupGCG​(p.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 0.00000991 in 1,211,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000047 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• 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 -3 ACMG points.

• PP5: Variant 8-132480483-T-TCGC is Pathogenic according to our data. Variant chr8-132480483-T-TCGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 538549.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ3	NM_004519.4	c.47_49dupGCG	p.Gly16dup	conservative_inframe_insertion	1/15	ENST00000388996.10	NP_004510.1
KCNQ3	XM_047421769.1	c.47_49dupGCG	p.Gly16dup	conservative_inframe_insertion	1/15		XP_047277725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10	c.47_49dupGCG	p.Gly16dup	conservative_inframe_insertion	1/15	1	NM_004519.4	ENSP00000373648.3
KCNQ3	ENST00000519445.5	c.47_49dupGCG	p.Gly16dup	conservative_inframe_insertion	1/15	5		ENSP00000428790.1

Frequencies

GnomAD3 genomes AF: 0.0000473 AC: 7 AN: 147890 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000173

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: 0.00

Gnomad OTH AF: 0.00

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

Gnomad4 AFR exome AF: 0.000139

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: 0.00000109

Gnomad4 OTH exome AF: 0.0000241

GnomAD4 genome AF: 0.0000473 AC: 7 AN: 147890 Hom.: 0 Cov.: 33 AF XY: 0.0000277 AC XY: 2 AN XY: 72080

Gnomad4 AFR AF: 0.000173

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Benign neonatal seizures Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 07, 2023

ClinVar contains an entry for this variant (Variation ID: 538549). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been observed in individuals with KCNQ3-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.47_49dup, results in the insertion of 1 amino acid(s) of the KCNQ3 protein (p.Gly16dup), but otherwise preserves the integrity of the reading frame. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2021

The c.47_49dupGCG (p.G16dup) alteration is located in exon 1 (coding exon 1) of the KCNQ3 gene. The alteration consists of an in-frame duplication of 3 nucleotides from position 47 to 49, resulting in the duplication of 1 residue. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 26, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In-frame insertion of one amino acid in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs981093917; hg19: chr8-133492730;