Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001040142.2(SCN2A):c.1526A>G (p.Lys509Arg)

CA318202

207086 (ClinVar)

Gene: SCN2A (HGNC:6326)

Condition: complex neurodevelopmental disorder (MONDO:0100038)

Inheritance Mode: Autosomal dominant inheritance

UUID: 20d691da-2b31-4fcc-bb92-9a9df416c0e6

Approved on: 2025-08-26

Published on: 2025-10-28

HGVS expressions

NM_001040142.2:c.1526A>G

NM_001040142.2(SCN2A):c.1526A>G (p.Lys509Arg)

NC_000002.12:g.165315613A>G

CM000664.2:g.165315613A>G

NC_000002.11:g.166172123A>G

CM000664.1:g.166172123A>G

NC_000002.10:g.165880369A>G

NG_008143.1:g.81212A>G

ENST00000631182.3:c.1526A>G

ENST00000375437.7:c.1526A>G

ENST00000635945.1:n.1889A>G

ENST00000636071.2:c.1526A>G

ENST00000636135.1:c.1397A>G

ENST00000636384.2:c.1526A>G

ENST00000636662.2:c.*2049A>G

ENST00000636769.1:c.1526A>G

ENST00000636985.2:c.1130A>G

ENST00000637266.2:c.1526A>G

ENST00000637367.1:c.*1459A>G

ENST00000638151.1:n.1610A>G

ENST00000283256.10:c.1526A>G

ENST00000375427.4:c.1526A>G

ENST00000375437.6:c.1526A>G

ENST00000480032.4:n.1669A>G

ENST00000631182.2:c.1526A>G

NM_001040142.1:c.1526A>G

NM_001040143.1:c.1526A>G

NM_021007.2:c.1526A>G

NM_001040143.2:c.1526A>G

NM_001371246.1:c.1526A>G

NM_001371247.1:c.1526A>G

NM_021007.3:c.1526A>G

Likely Benign

BS1 BP4

PS1 PP3 PP4 PM1 PM5 PM2

Evidence Links 0

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 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Epilepsy Sodium Channel VCEP

The filtering allele frequency (the lower threshold of the 95% CI of 21/1,613,966) of thec.1526A>G variant in SCN2A is 0.00001144 for Non-Finnish European chromosomes by gnomAD v4.1.0, which is higher than the ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel threshold (>0.0002%) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.243 (REVEL threshold for BP4 supporting 0.183-0.290, PMID: 36413997), evidence that does not predict a damaging effect on SCN2A function (BP4). This missense change has been observed in one individual with seizures (PMID: 25131622). However, the inheritance and a detailed information of the phenotype is not described. In summary, this variant has been classified as likely benign for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the Epilepsy Sodium Channel Expert Panel: BS1, BP4 (version 2.0; approved 8/26/25).

BS1

The filtering allele frequency (the lower threshold of the 95% CI of 21/1,613,966) of the c.1526A>G variant in SCN2A is 0.001144% (gnomAD v4.1.0) for Non-Finnish European chromosomes, which is higher than the ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel threshold (>0.0002%) for BS1, and therefore meets this criterion BS1).

BP4

The computational predictor REVEL gives a score of 0.243 (REVEL threshold for BP4 supporting 0.183-0.290, PMID: 36413997), evidence that does not predict a damaging effect on SCN2A function (BP4).

PS1

NM_001040142.2(SCN2A):c.1527A>G (p.Lys509=) synonymous Likely benign SCN1A: no paralogous variants SCN3A: no P/LP variants NM_006922.4(SCN3A):c.1516AGA[1] (p.Arg507del) VUS NM_006922.4(SCN3A):c.1521A>C (p.Arg507Ser) LB NM_006922.4(SCN3A):c.1520G>A (p.Arg507Lys) LB SCN8A: NM_001330260.2(SCN8A):c.1497G>A (p.Lys499=) LB

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4

Other phenotypes not consistent w/neurodevelopmental disorder: 0 points (for supporting 1-1.5 points) PMID: 25131622. WES in 78 patients with various neurodevelopmental disabilities. Patient 72 has the SCN2A c.1526 A>G (K509R) variant. However, the inheritance is unknown. Phenotype: only serizures, MRI findings: normal. They described epileptic encephalopathy, early infantile, 11 (MIM# 613721) as the disease. The phenotype evidence does not meet the complex Neurodevelopmental Disorder described by Helbig et al, 2018 (PMID: 30311377)

PM1

This variant does not reside within a region of SCN2A that is defined as a mutational hotspot or critical functional domain by the ClinGen Epilepsy Sodium Channel Expert Panel.

PM5

PM2

Allele frequency is above 0.0002% in GnomAD v4.1.0 (0.001144%)

Curation History

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