Variant: NM_001040142.2(SCN2A):c.1035-7A>G

CA2580064231

1342712 (ClinVar)

Gene: SCN2A

Condition: complex neurodevelopmental disorder

Inheritance Mode: Autosomal dominant inheritance

UUID: 2c861695-8d96-4b46-993f-583a560f62d8

Approved on: 2024-10-22

Published on: 2025-02-20

HGVS expressions

NM_001040142.2:c.1035-7A>G
NM_001040142.2(SCN2A):c.1035-7A>G
NC_000002.12:g.165313613A>G
CM000664.2:g.165313613A>G
NC_000002.11:g.166170123A>G
CM000664.1:g.166170123A>G
NC_000002.10:g.165878369A>G
NG_008143.1:g.79212A>G
ENST00000631182.3:c.1035-7A>G
ENST00000375437.7:c.1035-7A>G
ENST00000635945.1:n.1398-7A>G
ENST00000636071.2:c.1035-7A>G
ENST00000636135.1:c.906-7A>G
ENST00000636384.2:c.1035-7A>G
ENST00000636662.2:c.*1558-7A>G
ENST00000636769.1:c.1035-7A>G
ENST00000636985.2:c.639-7A>G
ENST00000637266.2:c.1035-7A>G
ENST00000637367.1:c.*968-7A>G
ENST00000638151.1:n.1119-7A>G
ENST00000283256.10:c.1035-7A>G
ENST00000375427.4:c.1035-7A>G
ENST00000375437.6:c.1035-7A>G
ENST00000424833.5:c.1035-7A>G
ENST00000480032.4:n.1178-7A>G
ENST00000631182.2:c.1035-7A>G
NM_001040142.1:c.1035-7A>G
NM_001040143.1:c.1035-7A>G
NM_021007.2:c.1035-7A>G
NM_001040143.2:c.1035-7A>G
NM_001371246.1:c.1035-7A>G
NM_001371247.1:c.1035-7A>G
NM_021007.3:c.1035-7A>G

Uncertain Significance

• Met criteria codes: PP3_Moderate PM6_Supporting PM2

• Not Met criteria codes: PS3

Expert Panel

Epilepsy Sodium Channel VCEP

Criteria Specification Information

Criteria Specification: ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN2A Version 1.0.0

Evidence submitted by expert panel

Epilepsy Sodium Channel VCEP

The c.1035-7A>G (NM_021007.3) variant in SCN2A is an intronic variant which is located in intron 8. The computational splicing predictor SpliceAI gives a score of [0.9] for acceptor loss and gain, predicting that the variant leads to the inclusion of 2 additional amino acids in exon 9 of SCN2A (PP3). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with early infantile epileptic encephalopathy (PM6_Supporting; PMID 35711923). This variant is absent from gnomAD v4.1 (PM2_Supporting). A minigene assay in HEK293T cells showed that this variant activated a cryptic intronic acceptor site leading to the elongation of intron 8 by 6 nucleotides, with a protein effect of p.Gly345_Gln346insTyrSer. However, this assay does not meet the requirements for use by the ClinGen Epilepsy Sodium Channel VCEP (PS3_Not Met). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for early infantile epileptic encephalopathy based on the ACMG/AMP criteria applied, as specified by theClinGen Epilepsy Sodium Channel VCEP: PM6_Supporting, PM2_Supporting, PP3. (Epilepsy Sodium Channel VCEP specifications v1.0; approved 10/22/2024).

Met criteria codes

• PP3_Moderate: The computational splicing predictor SpliceAI gives a score of [0.9] for acceptor loss and gain, predicting that the variant leads to the inclusion of 2 additional amino acids in exon 9 of SCN2A (PP3).
• PM6_Supporting: This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with early infantile epileptic encephalopathy (PM6_Supporting; PMID 35711923).
• PM2: This variant is absent from gnomAD v4.1 (PM2_Supporting).

Not Met criteria codes

• PS3: A minigene assay in HEK293T cells showed that this variant activated a cryptic intronic acceptor site leading to the elongation of intron 8 by 6 nucleotides, with a protein effect of p.Gly345_Gln346insTyrSer. However, this assay does not meet the requirements for use by the ClinGen Epilepsy Sodium Channel VCEP.