8-132480483-TCGCCGCCGC-T

Variant names:

• chr8-132480483-TCGCCGCCGC-T
• rs981093917
• NM_004519.4:c.41_49delGCGGCGGCG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BS1_Supporting

The NM_004519.4(KCNQ3):​c.41_49delGCGGCGGCG​(p.Gly14_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 0.0000165 in 1,211,130 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G14G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (1 hom.)
• Consequence: KCNQ3 NM_004519.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.896
• 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: Likely_benign. The variant received -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004519.4
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000179 (19/1063240) while in subpopulation SAS AF = 0.000576 (12/20818). AF 95% confidence interval is 0.000332. There are 1 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.41_49delGCGGCGGCG	p.Gly14_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.41_49delGCGGCGGCG	p.Gly14_Gly16del	disruptive_inframe_deletion	Exon 1 of 15	ENSP00000373648.3	O43525-1
	KCNQ3	ENST00000519445.5	TSL:5	c.41_49delGCGGCGGCG	p.Gly14_Gly16del	disruptive_inframe_deletion	Exon 1 of 15	ENSP00000428790.1	E7ET42
	KCNQ3	ENST00000519589.1	TSL:2	n.-182_-174delGCGGCGGCG		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00000676 AC: 1 AN: 147890 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000214

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000179 AC: 19 AN: 1063240 Hom.: 1 AF XY: 0.0000197 AC XY: 10 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: 0.000576 AC: 12 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: 0.00000657 AC: 6 AN: 913268

Other (OTH) AF: 0.0000241 AC: 1 AN: 41462

GnomAD4 genome AF: 0.00000676 AC: 1 AN: 147890 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 72080

African (AFR) AF: 0.00 AC: 0 AN: 40564

American (AMR) AF: 0.00 AC: 0 AN: 14914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.00 AC: 0 AN: 4918

South Asian (SAS) AF: 0.000214 AC: 1 AN: 4682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66562

Other (OTH) AF: 0.00 AC: 0 AN: 2036

Alfa AF: 0.00 Hom.: 0

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		0.90
Mutation Taster		=140/60	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;