Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001040142.2(SCN2A):c.1399G>A (p.Ala467Thr)

CA1939819

452471 (ClinVar)

Gene: SCN2A
Condition: complex neurodevelopmental disorder
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 1884e5f2-7fc9-4150-8381-123c9f745b24
Approved on: 2025-06-24
Published on: 2025-06-24

HGVS expressions

NM_001040142.2:c.1399G>A
NM_001040142.2(SCN2A):c.1399G>A (p.Ala467Thr)
NC_000002.12:g.165315486G>A
CM000664.2:g.165315486G>A
NC_000002.11:g.166171996G>A
CM000664.1:g.166171996G>A
NC_000002.10:g.165880242G>A
NG_008143.1:g.81085G>A
ENST00000631182.3:c.1399G>A
ENST00000375437.7:c.1399G>A
ENST00000635945.1:n.1762G>A
ENST00000636071.2:c.1399G>A
ENST00000636135.1:c.1270G>A
ENST00000636384.2:c.1399G>A
ENST00000636662.2:c.*1922G>A
ENST00000636769.1:c.1399G>A
ENST00000636985.2:c.1003G>A
ENST00000637266.2:c.1399G>A
ENST00000637367.1:c.*1332G>A
ENST00000638151.1:n.1483G>A
ENST00000283256.10:c.1399G>A
ENST00000375427.4:c.1399G>A
ENST00000375437.6:c.1399G>A
ENST00000424833.5:c.1399G>A
ENST00000480032.4:n.1542G>A
ENST00000631182.2:c.1399G>A
NM_001040142.1:c.1399G>A
NM_001040143.1:c.1399G>A
NM_021007.2:c.1399G>A
NM_001040143.2:c.1399G>A
NM_001371246.1:c.1399G>A
NM_001371247.1:c.1399G>A
NM_021007.3:c.1399G>A
More

Benign

Met criteria codes 2
BP4 BA1
Not Met criteria codes 13
PP1 PP3 PM6 PM2 PM1 PM5 BS4 BS3 BP2 PS2 PS4 PS3 PS1

Evidence Links 0

Expert Panel

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 NM_001040142.2(SCN2A):c.1399G>A variant in SCN2A is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 467 (p.Ala467Thr). The highest population minor allele frequency in gnomAD 4.1.0 is 0.01501% (9/59978 alleles) in the Admixed American population, which is higher than the ClinGen Epilepsy Sodium Channel VCEP threshold (>0.01%) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.269, (which is below the threshold of 0.290), evidence that does not predict a damaging effect on SCN2A function (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BP4, BA1. (Specification Version 2.0.0; 1/7/2025).
Met criteria codes
BP4
The computational predictor REVEL gives a score of 0.269, (which is below the threshold of 0.290), evidence that does not predict a damaging effect on SCN2A function (BP4).
BA1
The highest population minor allele frequency in gnomAD 4.1.0 is 0.01501% (9/59978 alleles) in the Admixed American population, which is higher than the ClinGen Epilepsy Sodium Channel VCEP threshold (>0.01%) for BA1, and therefore meets this criterion (BA1).
Not Met criteria codes
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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 VCEP.
PM5
5 different missense variants (SCN2A c.1399G>A p.Ala467Pro, SCN2A c.1393G>T p.Ala467Ser, SCN2A c.1400C>T p.Ala467Val, SCN1A c.1393A>G p.Thr465Ala, and SCN3A c.1397C>T p.Ser466Leu,) in the same or paralogous codon have been reported (ClinVar IDs: 2500543, 983216, 1318705, 1352508, and 3371473). However, these variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Epilepsy Sodium Channel VCEP.
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
To our knowledge, functional assays have not been reported for this variant.
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
This variant has been reported in one family and two additional probands meeting criteria for a complex neurodevelopmental disorder. However, PS4_Moderate cannot be applied because this variant is present in control populations (gnomAD, PMID 29635106, 38059254).
PS3
To our knowledge, functional assays have not been reported for this variant.
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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