rs1801475

Variant summary

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

The NM_172107.4(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
NM_172107.4 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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2
Missense variant in the KCNQ2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 319 curated pathogenic missense variants (we use a threshold of 10). The gene has 78 curated benign missense variants. Gene score misZ: 4.0411 (above the threshold of 3.09). Trascript score misZ: 3.6968 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank MANE Protein UniProt
KCNQ2NM_172107.4 linkc.2339A>C p.Asn780Thr missense_variant Exon 17 of 17 ENST00000359125.7 NP_742105.1 O43526-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNQ2ENST00000359125.7 linkc.2339A>C p.Asn780Thr missense_variant Exon 17 of 17 1 NM_172107.4 ENSP00000352035.2 O43526-1

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, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
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, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 25, 2013- -
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 testingGenome-Nilou LabAug 19, 2021- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsApr 26, 2017- -
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 04, 2025- -
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;.;.;.
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