8-132480483-TCGCCGCCGC-TCGC

Variant names:

• chr8-132480483-TCGCCGC-T
• rs981093917
• NM_004519.4:c.44_49delGCGGCG

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_49delGCGGCG​(p.Gly15_Gly16del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 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: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.858
• 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):

• 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: 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

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.44_49delGCGGCG	p.Gly15_Gly16del	disruptive_inframe_deletion	Exon 1 of 15	NP_004510.1	O43525-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	ENST00000388996.10	TSL:1 MANE Select	c.44_49delGCGGCG	p.Gly15_Gly16del	disruptive_inframe_deletion	Exon 1 of 15	ENSP00000373648.3	O43525-1
	KCNQ3	ENST00000519445.5	TSL:5	c.44_49delGCGGCG	p.Gly15_Gly16del	disruptive_inframe_deletion	Exon 1 of 15	ENSP00000428790.1	E7ET42
	KCNQ3	ENST00000519589.1	TSL:2	n.-179_-174delGCGGCG		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000282 AC: 3 AN: 1063240 Hom.: 0 AF XY: 0.00000197 AC XY: 1 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: 0.00000328 AC: 3 AN: 913268

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Benign neonatal seizures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.86
Mutation Taster		=171/29	polymorphism

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;