rs373780066

Positions:

• chr2-165354655-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1 PP2 BP4_Moderate BS2

The NM_001040142.2(SCN2A):​c.3383T>C​(p.Met1128Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.11

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 Likely_benign. Variant got -3 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 226) in uniprot entity SCN2A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001040142.2
• 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=0.16035366).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.3383T>C	p.Met1128Thr	missense_variant	17/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.3383T>C	p.Met1128Thr	missense_variant	17/27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.3383T>C	p.Met1128Thr	missense_variant	17/27	5	NM_001040142.2	ENSP00000364586	P1
SCN2A	ENST00000631182.3	c.3383T>C	p.Met1128Thr	missense_variant	17/27	5	NM_001371246.1	ENSP00000486885

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461434 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727024

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2017

The p.M1128T variant (also known as c.3383T>C), located in coding exon 16 of the SCN2A gene, results from a T to C substitution at nucleotide position 3383. The methionine at codon 1128 is replaced by threonine, an amino acid with similar properties. This alteration was detected in an individual with refractory, repetitive (100 per day) generalized convulsive seizures which onset at age 6. As seizures persisted, his intellect regressed and he is now severely intellectually delayed as an adult (Kobayashi K et al. Epilepsy Res., 2012 Nov;102:109-12). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1128 of the SCN2A protein (p.Met1128Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN2A-related conditions (PMID: 22591750, 32090326). ClinVar contains an entry for this variant (Variation ID: 589603). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SCN2A protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Benign	0.79
DEOGEN2	Uncertain	0.43	T;.;T;.;T;T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.062
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.27	T;.;T;.;.;.;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.045	N;N;.;N;N;N;N
MutationTaster	Benign	0.88	N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.2	N;.;.;.;.;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.42	T;.;.;.;.;T;T
Sift4G	Benign	0.70	T;.;.;T;.;T;T
Polyphen		0.0050	B;B;.;B;B;B;B
Vest4		0.51
MVP		0.94
ClinPred		0.28	T
GERP RS		5.6
Varity_R		0.16
gMVP		0.69

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: rs373780066; hg19: chr2-166211165;