8-132122143-G-A

Variant names:

• chr8-132122143-G-A
• rs2436126
• NM_004519.4:c.*7119C>T

Variant summary

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

The NM_004519.4(KCNQ3):​c.*7119C>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 152,168 control chromosomes in the GnomAD database, including 3,750 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3750 hom., cov: 32)
  • Exomes 𝑓: 0.22 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.523

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=-0.88).
• BP6: Variant 8-132122143-G-A is Benign according to our data. Variant chr8-132122143-G-A is described in ClinVar as [Benign]. Clinvar id is 361761.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 rank	MANE	Protein	UniProt
KCNQ3	NM_004519.4	c.*7119C>T		3_prime_UTR_variant	Exon 15 of 15	ENST00000388996.10	NP_004510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996	c.*7119C>T		3_prime_UTR_variant	Exon 15 of 15	1	NM_004519.4	ENSP00000373648.3

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31384 AN: 152034 Hom.: 3744 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: 0.00289

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.232

GnomAD4 exome AF: 0.222 AC: 4 AN: 18 Hom.: 0 Cov.: 0 AF XY: 0.222 AC XY: 4 AN XY: 18

Gnomad4 NFE exome AF: 0.222

GnomAD4 genome AF: 0.206 AC: 31394 AN: 152150 Hom.: 3750 Cov.: 32 AF XY: 0.203 AC XY: 15128 AN XY: 74362

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.295

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.218

Gnomad4 NFE AF: 0.269

Gnomad4 OTH AF: 0.230

Alfa AF: 0.248 Hom.: 2297

Bravo AF: 0.198

Asia WGS AF: 0.0990 AC: 348 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Seizures, benign familial neonatal, 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.8
DANN	Benign	0.58

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: rs2436126; hg19: chr8-133134390;