rs1801475

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The ENST00000359125.7(KCNQ2):​c.2339A>C​(p.Asn780Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,604,550 control chromosomes in the GnomAD database, including 328,384 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 27470 hom., cov: 35)
Exomes 𝑓: 0.64 ( 300914 hom. )

Consequence

KCNQ2
ENST00000359125.7 missense

Scores

1
17

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14O:2

Conservation

PhyloP100: 1.95
Variant links:
Genes affected
KCNQ2 (HGNC:6296): (potassium voltage-gated channel subfamily Q member 2) The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1). At least five transcript variants encoding five different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNQ2. . Gene score misZ 4.0411 (greater than the threshold 3.09). Trascript score misZ 3.6968 (greater than threshold 3.09). GenCC has associacion of gene with seizures, benign familial neonatal, 1, neonatal-onset developmental and epileptic encephalopathy, benign familial neonatal-infantile seizures, benign neonatal seizures, malignant migrating partial seizures of infancy, neonatal encephalopathy with non-epileptic myoclonus, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, developmental and epileptic encephalopathy, 7, benign familial infantile epilepsy.
BP4
Computational evidence support a benign effect (MetaRNN=7.1157156E-6).
BP6
Variant 20-63406924-T-G is Benign according to our data. Variant chr20-63406924-T-G is described in ClinVar as [Benign]. Clinvar id is 21779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63406924-T-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNQ2NM_172107.4 linkuse as main transcriptc.2339A>C p.Asn780Thr missense_variant 17/17 ENST00000359125.7 NP_742105.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNQ2ENST00000359125.7 linkuse as main transcriptc.2339A>C p.Asn780Thr missense_variant 17/171 NM_172107.4 ENSP00000352035 A1O43526-1

Frequencies

GnomAD3 genomes
AF:
0.595
AC:
90517
AN:
152022
Hom.:
27458
Cov.:
35
show subpopulations
Gnomad AFR
AF:
0.497
Gnomad AMI
AF:
0.647
Gnomad AMR
AF:
0.557
Gnomad ASJ
AF:
0.496
Gnomad EAS
AF:
0.638
Gnomad SAS
AF:
0.619
Gnomad FIN
AF:
0.652
Gnomad MID
AF:
0.601
Gnomad NFE
AF:
0.655
Gnomad OTH
AF:
0.588
GnomAD3 exomes
AF:
0.609
AC:
140836
AN:
231186
Hom.:
43252
AF XY:
0.614
AC XY:
77931
AN XY:
126864
show subpopulations
Gnomad AFR exome
AF:
0.495
Gnomad AMR exome
AF:
0.511
Gnomad ASJ exome
AF:
0.496
Gnomad EAS exome
AF:
0.623
Gnomad SAS exome
AF:
0.609
Gnomad FIN exome
AF:
0.654
Gnomad NFE exome
AF:
0.657
Gnomad OTH exome
AF:
0.624
GnomAD4 exome
AF:
0.642
AC:
931932
AN:
1452412
Hom.:
300914
Cov.:
66
AF XY:
0.640
AC XY:
462208
AN XY:
722134
show subpopulations
Gnomad4 AFR exome
AF:
0.490
Gnomad4 AMR exome
AF:
0.519
Gnomad4 ASJ exome
AF:
0.485
Gnomad4 EAS exome
AF:
0.639
Gnomad4 SAS exome
AF:
0.598
Gnomad4 FIN exome
AF:
0.657
Gnomad4 NFE exome
AF:
0.659
Gnomad4 OTH exome
AF:
0.615
GnomAD4 genome
AF:
0.595
AC:
90562
AN:
152138
Hom.:
27470
Cov.:
35
AF XY:
0.598
AC XY:
44509
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.497
Gnomad4 AMR
AF:
0.556
Gnomad4 ASJ
AF:
0.496
Gnomad4 EAS
AF:
0.639
Gnomad4 SAS
AF:
0.617
Gnomad4 FIN
AF:
0.652
Gnomad4 NFE
AF:
0.655
Gnomad4 OTH
AF:
0.583
Alfa
AF:
0.639
Hom.:
34024
Bravo
AF:
0.578
TwinsUK
AF:
0.662
AC:
2454
ALSPAC
AF:
0.658
AC:
2535
ESP6500AA
AF:
0.510
AC:
2225
ESP6500EA
AF:
0.644
AC:
5527
ExAC
AF:
0.604
AC:
72439
Asia WGS
AF:
0.613
AC:
2128
AN:
3476

ClinVar

Significance: Benign
Submissions summary: Benign:14Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:7
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 18, 2016- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 25, 2013- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingUnidad de Genómica Garrahan, Hospital de Pediatría GarrahanJul 15, 2024This variant is classified as Benign based on local population frequency. This variant was detected in 86% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 80. Only high quality variants are reported. -
Seizures, benign familial neonatal, 1 Benign:2Other:1
not provided, no classification providedliterature onlyGeneReviews-- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsApr 26, 2017- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 19, 2021- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxAug 28, 2020This variant is associated with the following publications: (PMID: 28038823) -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 31, 2015This 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. -
Early infantile epileptic encephalopathy with suppression bursts Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Developmental and epileptic encephalopathy, 7 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 19, 2021- -
Complex neurodevelopmental disorder Other:1
not provided, no classification providedliterature onlyChannelopathy-Associated Epilepsy Research Center-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.060
BayesDel_addAF
Benign
-0.77
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
9.5
DANN
Benign
0.47
DEOGEN2
Benign
0.0034
.;T;T;T;.;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.069
N
LIST_S2
Benign
0.0088
T;T;T;T;T;T
MetaRNN
Benign
0.0000071
T;T;T;T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.0
.;.;N;.;.;.
MutationTaster
Benign
1.0
P;P;P;P;P;P;P;P;P
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
0.61
.;.;N;.;N;.
REVEL
Benign
0.082
Sift
Benign
0.43
.;.;T;.;T;.
Sift4G
Benign
0.54
T;.;T;T;T;T
Polyphen
0.0
B;.;B;.;B;B
Vest4
0.041
MPC
0.64
ClinPred
0.00066
T
GERP RS
0.092
Varity_R
0.040
gMVP
0.18

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

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

Other links and lift over

dbSNP: rs1801475; hg19: chr20-62038277; COSMIC: COSV60540824; COSMIC: COSV60540824; API