8-132122041-G-A

Position:

• chr8-132122041-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000388996.10(KCNQ3):​c.*7221C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 152,204 control chromosomes in the GnomAD database, including 3,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3755 hom., cov: 32)
  • Exomes 𝑓: 0.23 (0 hom.)
• Consequence: KCNQ3 ENST00000388996.10 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.140

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-132122041-G-A is Benign according to our data. Variant chr8-132122041-G-A is described in ClinVar as [Benign]. Clinvar id is 361757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ3	NM_004519.4	c.*7221C>T		3_prime_UTR_variant	15/15	ENST00000388996.10	NP_004510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10	c.*7221C>T		3_prime_UTR_variant	15/15	1	NM_004519.4	ENSP00000373648	P1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31392 AN: 152042 Hom.: 3749 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.232

GnomAD4 exome AF: 0.227 AC: 10 AN: 44 Hom.: 0 Cov.: 0 AF XY: 0.143 AC XY: 4 AN XY: 28

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.500

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.206 AC: 31402 AN: 152160 Hom.: 3755 Cov.: 32 AF XY: 0.203 AC XY: 15137 AN XY: 74396

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.295

Gnomad4 EAS AF: 0.00250

Gnomad4 SAS AF: 0.231

Gnomad4 FIN AF: 0.219

Gnomad4 NFE AF: 0.269

Gnomad4 OTH AF: 0.230

Alfa AF: 0.235 Hom.: 573

Bravo AF: 0.198

Asia WGS AF: 0.0990 AC: 347 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Benign neonatal seizures Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	9.1
DANN	Benign	0.78

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: rs2436124; hg19: chr8-133134288;