rs150821246

chr8-132129618-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004519.4(KCNQ3):c.2263G>A(p.Asp755Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000486 in 1,614,058 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: KCNQ3 NM_004519.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10 O:1
• Conservation: PhyloP100: 4.36

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.060245782).
• BP6: Variant 8-132129618-C-T is Benign according to our data. Variant chr8-132129618-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 205988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132129618-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ3	NM_004519.4	c.2263G>A	p.Asp755Asn	missense_variant	15/15	ENST00000388996.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ3	ENST00000388996.10	c.2263G>A	p.Asp755Asn	missense_variant	15/15	1	NM_004519.4	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152090 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000374 AC: 94 AN: 251012 Hom.: 1 AF XY: 0.000376 AC XY: 51 AN XY: 135722

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000731

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000506 AC: 739 AN: 1461850 Hom.: 1 Cov.: 32 AF XY: 0.000498 AC XY: 362 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000630

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152208 Hom.: 1 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74402

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000622 Hom.: 0

Bravo AF: 0.000314

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000404 AC: 49

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000949

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	KCNQ3: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2021	This variant is associated with the following publications: (PMID: 18625963) -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 23, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Benign neonatal seizures Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Seizures, benign familial neonatal, 2 Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided, no classification provided	literature only	GeneReviews	-	Variant occurred in 2 sibs: 1 with rolandic epilepsy (no neonatal seizures), 1 with EEG features (CTS) but no seizures. Also occurred in the unaffected mother and was absent in a sib with rolandic epilepsy; is present in 0.07% of Europeans, incl 1 homozygous individual (ExAC) -

Childhood epilepsy with centrotemporal spikes Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

KCNQ3-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 01, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;.;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.060	T;T;T;T;T
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.1	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.88	N;.;N;N;.
REVEL	Uncertain	0.40
Sift	Benign	0.16	T;.;T;T;.
Sift4G	Benign	0.34	T;T;T;T;.
Polyphen		1.0	D;.;.;D;.
Vest4		0.36
MVP		0.81
MPC		0.44
ClinPred		0.14	T
GERP RS		5.3
Varity_R		0.14
gMVP		0.51

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: rs150821246; hg19: chr8-133141865;