rs74582884

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_004519.4(KCNQ3):​c.1720C>T​(p.Pro574Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,612,916 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 4 hom., cov: 31)
Exomes 𝑓: 0.0028 ( 9 hom. )

Consequence

KCNQ3
NM_004519.4 missense

Scores

9
4
6

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17O:1

Conservation

PhyloP100: 9.32
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, phyloP100way_vertebrate, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PROVEAN was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.01873827).
BP6
Variant 8-132134369-G-A is Benign according to our data. Variant chr8-132134369-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 21411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132134369-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00246 (374/152208) while in subpopulation AMR AF= 0.0053 (81/15282). AF 95% confidence interval is 0.00437. There are 4 homozygotes in gnomad4. There are 188 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 374 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNQ3NM_004519.4 linkc.1720C>T p.Pro574Ser missense_variant Exon 13 of 15 ENST00000388996.10 NP_004510.1 O43525-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNQ3ENST00000388996.10 linkc.1720C>T p.Pro574Ser missense_variant Exon 13 of 15 1 NM_004519.4 ENSP00000373648.3 O43525-1

Frequencies

GnomAD3 genomes
AF:
0.00246
AC:
374
AN:
152090
Hom.:
4
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000628
Gnomad AMI
AF:
0.00439
Gnomad AMR
AF:
0.00531
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00366
Gnomad OTH
AF:
0.00335
GnomAD3 exomes
AF:
0.00212
AC:
534
AN:
251432
Hom.:
1
AF XY:
0.00206
AC XY:
280
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.000800
Gnomad AMR exome
AF:
0.00263
Gnomad ASJ exome
AF:
0.000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000323
Gnomad NFE exome
AF:
0.00346
Gnomad OTH exome
AF:
0.00326
GnomAD4 exome
AF:
0.00277
AC:
4049
AN:
1460708
Hom.:
9
Cov.:
30
AF XY:
0.00274
AC XY:
1990
AN XY:
726748
show subpopulations
Gnomad4 AFR exome
AF:
0.000926
Gnomad4 AMR exome
AF:
0.00262
Gnomad4 ASJ exome
AF:
0.00115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.000318
Gnomad4 NFE exome
AF:
0.00332
Gnomad4 OTH exome
AF:
0.00263
GnomAD4 genome
AF:
0.00246
AC:
374
AN:
152208
Hom.:
4
Cov.:
31
AF XY:
0.00253
AC XY:
188
AN XY:
74412
show subpopulations
Gnomad4 AFR
AF:
0.000626
Gnomad4 AMR
AF:
0.00530
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.00366
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.00345
Hom.:
1
Bravo
AF:
0.00250
TwinsUK
AF:
0.00351
AC:
13
ALSPAC
AF:
0.00259
AC:
10
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00372
AC:
32
ExAC
AF:
0.00199
AC:
242
EpiCase
AF:
0.00393
EpiControl
AF:
0.00397

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:17Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 25, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate no damaging effect, specifically, voltage clamp analysis revealed no significant reduction in potassium current as compared to wildtype (Neubauer et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28351718, 20981092, 18625963, 19344764, 23596459, 25784856, 28488083, 27875746, 29948376) -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

KCNQ3: PM5, BS2 -

Seizures, benign familial neonatal, 2 Benign:4Other:1
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

Allele is present at 0.3% in non-Finnish Europeans and 0.2% in Latinos (gnomAD). Overrepresented (p=0.008) in idiopathic generalized epilepsies (8/455 persons). Detected in other complex phenotypes; in 4 persons with rolandic epilepsy and in 1 with rolandic epilepsy and moderate psychomotor delay; in 3 persons with autism spectrum disorders and no additional neurologic features -

Mar 06, 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. -

Mar 05, 2018
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 23, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:3
Feb 01, 2024
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 31, 2016
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 03, 2014
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Dec 29, 2018
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

KCNQ3-related disorder Benign:1
Oct 11, 2019
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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). -

Benign Neonatal Epilepsy Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Benign neonatal seizures Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Intellectual disability Benign:1
Apr 20, 2020
Diagnostic Laboratory, Strasbourg University Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.31
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.76
D;.;.;.;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.96
D;D;D;D;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Benign
0.019
T;T;T;T;T
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Uncertain
2.1
M;.;.;.;.
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-1.1
N;.;N;N;.
REVEL
Pathogenic
0.83
Sift
Benign
0.11
T;.;T;T;.
Sift4G
Benign
0.092
T;T;T;T;.
Polyphen
1.0
D;.;.;D;.
Vest4
0.67
MVP
0.89
MPC
0.51
ClinPred
0.037
T
GERP RS
5.5
Varity_R
0.17
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs74582884; hg19: chr8-133146616; API