20-63438645-G-C
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Moderate
The NM_172107.4(KCNQ2):c.1003C>G(p.Pro335Ala) variant causes a missense change involving the alteration of a 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P335S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_172107.4 missense
Scores
Clinical Significance
Conservation
Publications
- 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
Genome browser will be placed here
ACMG classification
Our verdict: Pathogenic. The variant received 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro335 amino acid residue in KCNQ2. Another variant that disrupts this residue has been observed in affected individuals (Invitae, PMID: 28867141), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed to be de novo in an individual affected with early infantile epileptic encephalopathy (PMID: Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with alanine at codon 335 of the KCNQ2 protein (p.Pro335Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at