20-63407176-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_172107.4(KCNQ2):​c.2087C>T​(p.Thr696Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000474 in 1,604,172 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

KCNQ2
NM_172107.4 missense

Scores

1
2
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.0140
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 -12 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=0.023257107).
BP6
Variant 20-63407176-G-A is Benign according to our data. Variant chr20-63407176-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461412.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000525 (8/152334) while in subpopulation AMR AF= 0.000261 (4/15312). AF 95% confidence interval is 0.0000887. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNQ2NM_172107.4 linkc.2087C>T p.Thr696Met 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.2087C>T p.Thr696Met missense_variant Exon 17 of 17 1 NM_172107.4 ENSP00000352035.2 O43526-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000246
AC:
57
AN:
231844
Hom.:
1
AF XY:
0.000164
AC XY:
21
AN XY:
128124
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00157
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000671
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000191
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000468
AC:
68
AN:
1451838
Hom.:
1
Cov.:
36
AF XY:
0.0000374
AC XY:
27
AN XY:
722304
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00122
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000350
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000811
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152334
Hom.:
0
Cov.:
33
AF XY:
0.0000671
AC XY:
5
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000292
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.000116
AC:
14

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 06, 2017- -
Benign, criteria provided, single submitterclinical testingGeneDxJun 04, 2021- -
Early infantile epileptic encephalopathy with suppression bursts Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 03, 2025- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
4.0
DANN
Benign
0.96
DEOGEN2
Benign
0.29
.;T;T;T;T;T;T;.;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.036
N
LIST_S2
Uncertain
0.91
D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.44
D
MetaRNN
Benign
0.023
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.65
D
MutationAssessor
Benign
-0.11
.;.;.;.;.;N;.;.;.
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-1.0
.;.;.;N;.;N;.;N;.
REVEL
Benign
0.29
Sift
Benign
0.18
.;.;.;T;.;T;.;T;.
Sift4G
Benign
0.17
T;T;T;T;.;T;T;T;T
Polyphen
0.0040
B;.;.;.;.;B;.;B;B
Vest4
0.052
MutPred
0.15
.;.;.;.;.;Loss of glycosylation at S695 (P = 0.0661);.;.;.;
MVP
0.56
MPC
0.65
ClinPred
0.031
T
GERP RS
-4.8
Varity_R
0.021
gMVP
0.26

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: rs570139975; hg19: chr20-62038529; API