rs769825203

Variant names:

• chr2-165315472-C-A
• rs769825203
• NM_001040142.2:c.1385C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-165315472-C-A
• chr2-165315472-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001040142.2(SCN2A):​c.1385C>A​(p.Ala462Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,464 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A462V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN2A NM_001040142.2 missense, splice_region
• Scores: Splicing: ADA: 0.09788
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.48
• Publications: 3 publications found

Genes affected

SCN2A (HGNC:10588): (sodium voltage-gated channel alpha subunit 2) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

SCN2A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• developmental and epileptic encephalopathy, 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• episodic ataxia, type 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign familial neonatal-infantile seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SCN2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 362 curated pathogenic missense variants (we use a threshold of 10). The gene has 36 curated benign missense variants. Trascript score misZ: 8.7114 (above the threshold of 3.09). GenCC associations: The gene is linked to genetic developmental and epileptic encephalopathy, episodic ataxia, type 9, seizures, benign familial infantile, 3, complex neurodevelopmental disorder, benign familial neonatal-infantile seizures, Dravet syndrome, infantile spasms, developmental and epileptic encephalopathy, 11, intellectual disability, benign familial infantile epilepsy, malignant migrating partial seizures of infancy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.1385C>A	p.Ala462Glu	missense_variant, splice_region_variant	Exon 11 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.1385C>A	p.Ala462Glu	missense_variant, splice_region_variant	Exon 11 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.1385C>A	p.Ala462Glu	missense_variant, splice_region_variant	Exon 11 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.1385C>A	p.Ala462Glu	missense_variant, splice_region_variant	Exon 11 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.1385C>A	p.Ala462Glu	missense_variant, splice_region_variant	Exon 11 of 27	1		ENSP00000283256.6
SCN2A	ENST00000424833.5	c.1385C>A	p.Ala462Glu	missense_variant, splice_region_variant	Exon 11 of 11	1		ENSP00000406454.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248128 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000902

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461464 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727032

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111736

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Uncertain:1

Sep 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 462 of the SCN2A protein (p.Ala462Glu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 2636978). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

SCN2A-related disorder Uncertain:1

Oct 19, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN2A c.1385C>A variant is predicted to result in the amino acid substitution p.Ala462Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-166171982-C-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.68	.;D;.;T;.;D;D;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;T;.;T;.;.;.;T
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.1	.;M;M;.;M;M;M;M
PhyloP100		5.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N;D;.;.;.;.;D;D
REVEL	Uncertain	0.49
Sift	Benign	0.11	T;D;.;.;.;.;D;D
Sift4G	Benign	0.074	T;T;.;.;T;.;T;T
Polyphen		0.34, 0.0030	.;B;B;.;B;B;B;B
Vest4		0.68, 0.67, 0.65, 0.65
MutPred		0.42		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);.;Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP		0.97
ClinPred		0.36	T
GERP RS		5.9
Varity_R		0.35
gMVP		0.93
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.098
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs769825203; hg19: chr2-166171982; COSMIC: COSV51847689; COSMIC: COSV51847689;