8-132122131-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004519.4(KCNQ3):c.*7131G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0526 in 152,288 control chromosomes in the GnomAD database, including 273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.053 (273 hom., cov: 32)
  • Exomes 𝑓: 0.10 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -2.28

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 8-132122131-C-T is Benign according to our data. Variant chr8-132122131-C-T is described in ClinVar as [Benign]. Clinvar id is 361760.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ3	NM_004519.4	c.*7131G>A		3_prime_UTR_variant	15/15	ENST00000388996.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ3	ENST00000388996.10	c.*7131G>A		3_prime_UTR_variant	15/15	1	NM_004519.4	P1

Frequencies

GnomAD3 genomes AF: 0.0526 AC: 8001 AN: 152130 Hom.: 273 Cov.: 32

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0353

Gnomad ASJ AF: 0.0600

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0913

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0786

Gnomad OTH AF: 0.0470

GnomAD4 exome AF: 0.100 AC: 4 AN: 40 Hom.: 0 Cov.: 0 AF XY: 0.125 AC XY: 4 AN XY: 32

Gnomad4 EAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.105

GnomAD4 genome AF: 0.0526 AC: 8004 AN: 152248 Hom.: 273 Cov.: 32 AF XY: 0.0518 AC XY: 3855 AN XY: 74424

Gnomad4 AFR AF: 0.0173

Gnomad4 AMR AF: 0.0352

Gnomad4 ASJ AF: 0.0600

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0178

Gnomad4 FIN AF: 0.0913

Gnomad4 NFE AF: 0.0786

Gnomad4 OTH AF: 0.0465

Alfa AF: 0.0611 Hom.: 31

Bravo AF: 0.0476

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Seizures, benign familial neonatal, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Benign neonatal seizures Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.017
Dann	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs75865310; hg19: chr8-133134378;