rs765714006

Positions:

• chr2-165310472-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001040142.2(SCN2A):​c.847C>G​(p.Pro283Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P283P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN2A

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.847C>G	p.Pro283Ala	missense_variant	7/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.847C>G	p.Pro283Ala	missense_variant	7/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.847C>G	p.Pro283Ala	missense_variant	7/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.847C>G	p.Pro283Ala	missense_variant	7/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251218 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461376 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726988

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 283 of the SCN2A protein (p.Pro283Ala). This variant is present in population databases (rs765714006, gnomAD 0.006%). 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: 533491). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN2A protein function. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2019

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; Has not been previously published as pathogenic or benign to our knowledge; This substitution is predicted to be within the pore forming loop between the S5 and S6 transmembrane segments of the first homologous domain -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;.;D;.;.;.;D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationTaster	Benign	0.92	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.5	D;D;.;.;.;.;D;D;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.020	D;T;.;.;.;.;T;T;.
Sift4G	Benign	0.53	T;T;.;.;T;.;T;T;T
Polyphen		0.29, 0.13	.;B;B;.;B;B;B;B;.
Vest4		0.41, 0.47, 0.42, 0.42
MutPred		0.69		Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);.;Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);.;
MVP		0.96
ClinPred		0.54	D
GERP RS		5.3
Varity_R		0.22
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs765714006; hg19: chr2-166166982;