rs1553567409

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP2PP3PP5_Very_Strong

The NM_001040142.2(SCN2A):c.605C>T(p.Ala202Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SCN2A
NM_001040142.2 missense, splice_region

Scores

Splicing: ADA: 0.9838

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 7.91

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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 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.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 2-165308794-C-T is Pathogenic according to our data. Variant chr2-165308794-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2 link	c.605C>T	p.Ala202Val	missense_variant, splice_region_variant	Exon 5 of 27	ENST00000375437.7	NP_001035232.1	Q99250-1
SCN2A	NM_001371246.1 link	c.605C>T	p.Ala202Val	missense_variant, splice_region_variant	Exon 5 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN2A	ENST00000375437.7 link	c.605C>T	p.Ala202Val	missense_variant, splice_region_variant	Exon 5 of 27	5	NM_001040142.2	ENSP00000364586.2	Q99250-1
SCN2A	ENST00000631182.3 link	c.605C>T	p.Ala202Val	missense_variant, splice_region_variant	Exon 5 of 27	5	NM_001371246.1	ENSP00000486885.1	Q99250-2
SCN2A	ENST00000283256.10 link	c.605C>T	p.Ala202Val	missense_variant, splice_region_variant	Exon 5 of 27	1		ENSP00000283256.6	Q99250-1
SCN2A	ENST00000424833.5 link	c.605C>T	p.Ala202Val	missense_variant, splice_region_variant	Exon 5 of 11	1		ENSP00000406454.2	F6U291

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460274

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726468

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 11

Pathogenic:3

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.A202V in SCN2A (NM_021007.3) has been reported previously in an individual affected with benign familial neonatal seizures (Wolff et al, 2017). The p.A202V variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Ala at position 202 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The p.A202V missense variant is predicted to be damaging by both SIFT and PolyPhen2. The alanine residue at codon 202 of SCN2A is conserved in all mammalian species. The nucleotide c.605 in SCN2A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -

Mar 05, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.86 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000449147 /PMID: 28379373). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:2

Jun 14, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in a patient with myoclonic epilepsy and febrile seizures and in a patient with early-onset catatonic syndrome; however, no segregation information was provided (Vykuntaraju K. Gowda et al., 2021; Leroy A et al., 2018); Reported as a maternally inherited variant in a patient with benign familial neonatal seizures (Wolff et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the transmembrane segment S3 of the first homologous domain; This variant is associated with the following publications: (PMID: 32090326, Wu_2021, 30381472, 34782754, 31440721, Gowda_2021, Nieto-Barcelo_2021, 28379373, 35431799, 35715422) -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN2A: PM1, PM2, PM5, PS2:Moderate, PS4:Moderate, PP3, PP4 -

Seizures, benign familial infantile, 3

Pathogenic:2

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Sep 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 202 of the SCN2A protein (p.Ala202Val). 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: 28379373, 30381472, 34782754; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 449147). 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 disruptive. For these reasons, this variant has been classified as Pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Feb 16, 2022

Neurology Department, Shenzhen Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

History of neurodevelopmental disorder

Uncertain:1

Feb 15, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The c.605C>T variant (also known as p.A202V), located in coding exon 4 of the SCN2A gene, results from a C to T substitution at nucleotide position 605. The amino acid change results in alanine to valine at codon 202, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6498 samples (12996 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. This amino acid alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. In addition, using theBDGPandESEfindersplice site prediction tools, this nucleotidealteration is not predicted to have any significant effect on this splice donor site; however, direct evidence is unavailable.Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

.;D;.;T;.;D;D;.;T

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;.;D;.;.;.;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.90

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

.;H;H;.;H;H;H;H;.

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.9

D;D;.;.;.;.;D;D;.

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;D;.;.;.;.;D;D;.

Sift4G

Pathogenic

0.0010

D;D;.;.;D;.;D;D;D

Polyphen

0.99, 0.99

.;D;D;.;D;D;D;D;.

Vest4

0.70, 0.70, 0.70, 0.71

MutPred

0.74

Loss of catalytic residue at A202 (P = 0.1336);Loss of catalytic residue at A202 (P = 0.1336);Loss of catalytic residue at A202 (P = 0.1336);.;Loss of catalytic residue at A202 (P = 0.1336);Loss of catalytic residue at A202 (P = 0.1336);Loss of catalytic residue at A202 (P = 0.1336);Loss of catalytic residue at A202 (P = 0.1336);.;

MVP

0.98

ClinPred

0.99

GERP RS

5.6

Varity_R

0.93

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over