2-165315472-C-T

Position:

• chr2-165315472-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_001040142.2(SCN2A):​c.1385C>T​(p.Ala462Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000411 in 1,461,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: SCN2A NM_001040142.2 missense, splice_region
• Scores: Splicing: ADA: 0.02364
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.48

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN2A. . Trascript score misZ 8.7114 (greater than threshold 3.09). GenCC has associacion of gene with seizures, benign familial infantile, 3, Dravet syndrome, benign familial neonatal-infantile seizures, malignant migrating partial seizures of infancy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 11, developmental and epileptic encephalopathy, West syndrome, benign familial infantile epilepsy, episodic ataxia, type 9.
• BP4: Computational evidence support a benign effect (MetaRNN=0.423316).
• BS2: High AC in GnomAdExome4 at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.1385C>T	p.Ala462Val	missense_variant, splice_region_variant	11/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.1385C>T	p.Ala462Val	missense_variant, splice_region_variant	11/27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.1385C>T	p.Ala462Val	missense_variant, splice_region_variant	11/27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.1385C>T	p.Ala462Val	missense_variant, splice_region_variant	11/27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.1385C>T	p.Ala462Val	missense_variant, splice_region_variant	11/27	1		ENSP00000283256.6
SCN2A	ENST00000424833.5	c.1385C>T	p.Ala462Val	missense_variant, splice_region_variant	11/11	1		ENSP00000406454.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000322 AC: 8 AN: 248128 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134542

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000541

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000411 AC: 60 AN: 1461464 Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33 AN XY: 727032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 23, 2022	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 586495). This missense change has been observed in individual(s) with autism spectrum disorder (PMID: 30564305). This variant is present in population databases (rs769825203, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 462 of the SCN2A protein (p.Ala462Val). -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2020	The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This substitution is predicted to be within the cytoplasmic loop between the first and second homologous domains; This variant is associated with the following publications: (PMID: 30564305) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	.;D;.;T;.;D;D;.
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;.;D;.;.;.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.7	.;L;L;.;L;L;L;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.6	D;N;.;.;.;.;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.098	T;T;.;.;.;.;T;T
Sift4G	Benign	0.11	T;T;.;.;T;.;T;T
Polyphen		0.0030, 0.0070	.;B;B;.;B;B;B;B
Vest4		0.52, 0.53, 0.53, 0.54
MutPred		0.42		Gain of catalytic residue at A462 (P = 0.0366);Gain of catalytic residue at A462 (P = 0.0366);Gain of catalytic residue at A462 (P = 0.0366);.;Gain of catalytic residue at A462 (P = 0.0366);Gain of catalytic residue at A462 (P = 0.0366);Gain of catalytic residue at A462 (P = 0.0366);Gain of catalytic residue at A462 (P = 0.0366);
MVP		0.94
ClinPred		0.11	T
GERP RS		5.9
Varity_R		0.071
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.024
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs769825203; hg19: chr2-166171982; COSMIC: COSV51849419; COSMIC: COSV51849419;