rs1057516110
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP2PP3
The NM_172107.4(KCNQ2):c.1073C>T(p.Ser358Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S358P) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 33)
Consequence
KCNQ2
NM_172107.4 missense
NM_172107.4 missense
Scores
10
7
2
Clinical Significance
Conservation
PhyloP100: 3.21
Publications
1 publications found
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]
KCNQ2 Gene-Disease associations (from GenCC):
- complex neurodevelopmental disorderInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- developmental and epileptic encephalopathy, 7Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
- neonatal encephalopathy with non-epileptic myoclonusInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- neonatal-onset developmental and epileptic encephalopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- seizures, benign familial neonatal, 1Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
- seizures, benign familial neonatal, 2Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- benign familial infantile epilepsyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- benign familial neonatal-infantile seizuresInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- benign neonatal seizuresInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- malignant migrating partial seizures of infancyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
PM1
In a hotspot region, there are 25 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_172107.4
PM2
Very rare variant in population databases, with high coverage;
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 benign familial infantile epilepsy, malignant migrating partial seizures of infancy, developmental and epileptic encephalopathy, 7, benign familial neonatal-infantile seizures, benign neonatal seizures, neonatal-onset developmental and epileptic encephalopathy, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, seizures, benign familial neonatal, 1, neonatal encephalopathy with non-epileptic myoclonus.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.748
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link
Submissions by phenotype
Seizures, benign familial neonatal, 1 Other:1
-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only
BFNE (benign familial neonatal epilepsy) -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;.;T;T;T;T;D;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.;.;.;.;M;.;M;M;M
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;.;.;.;D;.;D;.;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
.;.;.;.;D;.;D;.;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;.;D;D;D;D;D
Polyphen
D;.;.;.;.;.;D;.;D;D;.
Vest4
MutPred
Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;Loss of helix (P = 0.079);.;Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP
MPC
2.2
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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