rs114095081

chr8-132129575-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004519.4(KCNQ3):c.2306C>A(p.Pro769His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,614,174 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (15 hom.)
• Consequence: KCNQ3 NM_004519.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.46

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 (MetaRNN=0.008564889).
• BP6: Variant 8-132129575-G-T is Benign according to our data. Variant chr8-132129575-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 138051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132129575-G-T is described in Lovd as [Likely_benign]. Variant chr8-132129575-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00649 (988/152294) while in subpopulation AFR AF= 0.0203 (842/41552). AF 95% confidence interval is 0.0191. There are 13 homozygotes in gnomad4. There are 471 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 989 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ3	NM_004519.4	c.2306C>A	p.Pro769His	missense_variant	15/15	ENST00000388996.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ3	ENST00000388996.10	c.2306C>A	p.Pro769His	missense_variant	15/15	1	NM_004519.4	P1

Frequencies

GnomAD3 genomes AF: 0.00650 AC: 989 AN: 152174 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00248 AC: 623 AN: 251144 Hom.: 5 AF XY: 0.00197 AC XY: 267 AN XY: 135746

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000793

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00131 AC: 1911 AN: 1461880 Hom.: 15 Cov.: 32 AF XY: 0.00126 AC XY: 915 AN XY: 727242

Gnomad4 AFR exome AF: 0.0218

Gnomad4 AMR exome AF: 0.00369

Gnomad4 ASJ exome AF: 0.00298

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000584

Gnomad4 OTH exome AF: 0.00306

GnomAD4 genome AF: 0.00649 AC: 988 AN: 152294 Hom.: 13 Cov.: 32 AF XY: 0.00632 AC XY: 471 AN XY: 74470

Gnomad4 AFR AF: 0.0203

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00344 Hom.: 2

Bravo AF: 0.00787

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0263 AC: 116

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00268 AC: 326

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Seizures, benign familial neonatal, 2 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Feb 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 22, 2013

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2016

This alteration is classified as 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. -

Benign Neonatal Epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Benign neonatal seizures Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;.;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T;T;T;T
MetaRNN	Benign	0.0086	T;T;T;T;T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	1.1	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.90	N;.;N;N;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.020	D;.;D;D;.
Sift4G	Benign	0.11	T;T;T;T;.
Polyphen		1.0	D;.;.;D;.
Vest4		0.35
MVP		0.43
MPC		0.42
ClinPred		0.028	T
GERP RS		5.1
Varity_R		0.15
gMVP		0.34

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: rs114095081; hg19: chr8-133141822; COSMIC: COSV99073704;