rs794727152
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS2PS3PP3_ModeratePM2_SupportingPM1
This summary comes from the ClinGen Evidence Repository: The c.2558G>A variant in SCN2A is a missense variant predicted to cause subsitution of arginine by glutamine at amino acid 853 (p.Arg853Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in at least 4 individual(s) identified in the published literature (PMIDs: 23935176 , 23934111, 31139143, 28708303], with additional evidence published reports available (PS2). It is absent from gnomAD v2.1.1 (PM2_Supporting). Heterologous expression assay with voltage clamping showed a decrease in peak current of 51%, which is below the threshold of 72.1%, evidence that correlates with PS3. It is a missense variant that resides within a pathogenic enriched region that is defined as a mutational hotspot (PM1). The computational predictor REVEL gives a score of 0.95, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as PATHOGENIC for AUTOSOMAL DOMINANT COMPLEX NEURODEVELOPMENTAL DISORDER based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS2, PS3, PP3_Moderate, PM2_Supporting. (Epilepsy Sodium Channel VCEP specifications version 1.0) LINK:https://erepo.genome.network/evrepo/ui/classification/CA210022/MONDO:0100038/068
Frequency
Consequence
NM_001040142.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.2558G>A | p.Arg853Gln | missense_variant | 15/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.2558G>A | p.Arg853Gln | missense_variant | 15/27 | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.2558G>A | p.Arg853Gln | missense_variant | 15/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.2558G>A | p.Arg853Gln | missense_variant | 15/27 | 5 | NM_001371246.1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 11 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | UCLA Clinical Genomics Center, UCLA | Jun 18, 2013 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 19, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris | Jan 06, 2017 | Intellectual disability.severe; epilepsy (spasms); dysmorphism - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 18, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 31, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 12, 2021 | Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26482601, 32090326, 24866042, 25772804, 23935176, 25459969, 23934111, 29056246, 28708303, 28628100, 28379373, 29186148, 30174244, 29844171, 30619928, 29655203, 31139143, 31558572, 32860008, 32005694, 33278787, 31031587, 31175295, 33731876, 34093402, 34287911) - |
Complex neurodevelopmental disorder Pathogenic:2Other:1
Pathogenic, reviewed by expert panel | curation | ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen | May 09, 2023 | The c.2558G>A variant in SCN2A is a missense variant predicted to cause subsitution of arginine by glutamine at amino acid 853 (p.Arg853Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in at least 4 individual(s) identified in the published literature (PMIDs: 23935176 , 23934111, 31139143, 28708303], with additional evidence published reports available (PS2). It is absent from gnomAD v2.1.1 (PM2_Supporting). Heterologous expression assay with voltage clamping showed a decrease in peak current of 51%, which is below the threshold of 72.1%, evidence that correlates with PS3. It is a missense variant that resides within a pathogenic enriched region that is defined as a mutational hotspot (PM1). The computational predictor REVEL gives a score of 0.95, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as PATHOGENIC for AUTOSOMAL DOMINANT COMPLEX NEURODEVELOPMENTAL DISORDER based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS2, PS3, PP3_Moderate, PM2_Supporting. (Epilepsy Sodium Channel VCEP specifications version 1.0) - |
Pathogenic, no assertion criteria provided | provider interpretation | GenomeConnect - Simons Searchlight | Jan 16, 2019 | Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-01-16 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. - |
not provided, no classification provided | literature only | Channelopathy-Associated Epilepsy Research Center | - | - - |
Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 07, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 853 of the SCN2A protein (p.Arg853Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with West syndrome (PMID: 23935176, 25772804, 28379373, 29186148). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 194555). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN2A protein function. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
West syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Neurology Department, Shenzhen Children's Hospital | Feb 16, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at