NM_001040142.2:c.562C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 7P and 4B. PM1PP2PP3_StrongBS2

The NM_001040142.2(SCN2A):​c.562C>T​(p.Arg188Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000322 in 1,460,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. 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. R188Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

SCN2A
NM_001040142.2 missense

Scores

16
2
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3

Conservation

PhyloP100: 3.95

Publications

25 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_001040142.2
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.95
BS2
High AC in GnomAdExome4 at 47 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN2ANM_001040142.2 linkc.562C>T p.Arg188Trp missense_variant Exon 5 of 27 ENST00000375437.7 NP_001035232.1 Q99250-1
SCN2ANM_001371246.1 linkc.562C>T p.Arg188Trp missense_variant Exon 5 of 27 ENST00000631182.3 NP_001358175.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN2AENST00000375437.7 linkc.562C>T p.Arg188Trp missense_variant Exon 5 of 27 5 NM_001040142.2 ENSP00000364586.2 Q99250-1
SCN2AENST00000631182.3 linkc.562C>T p.Arg188Trp missense_variant Exon 5 of 27 5 NM_001371246.1 ENSP00000486885.1 Q99250-2
SCN2AENST00000283256.10 linkc.562C>T p.Arg188Trp missense_variant Exon 5 of 27 1 ENSP00000283256.6 Q99250-1
SCN2AENST00000424833.5 linkc.562C>T p.Arg188Trp missense_variant Exon 5 of 11 1 ENSP00000406454.2 F6U291

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.0000199
AC:
5
AN:
250874
AF XY:
0.0000221
show subpopulations
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:
0.0000441
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000322
AC:
47
AN:
1460562
Hom.:
0
Cov.:
31
AF XY:
0.0000344
AC XY:
25
AN XY:
726608
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33440
American (AMR)
AF:
0.00
AC:
0
AN:
44688
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26084
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39628
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86230
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53372
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.0000405
AC:
45
AN:
1111034
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60322
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00000890
Hom.:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Seizures, benign familial infantile, 3 Pathogenic:1
Apr 01, 2004
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Inborn genetic diseases Uncertain:1
Aug 03, 2021
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.562C>T (p.R188W) alteration is located in exon 5 (coding exon 4) of the SCN2A gene. This alteration results from a C to T substitution at nucleotide position 562, causing the arginine (R) at amino acid position 188 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Uncertain:1
Sep 07, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 12875). This missense change has been observed in individual(s) with febrile seizures associated with afebrile seizures (PMID: 11371648, 15301839). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 188 of the SCN2A protein (p.Arg188Trp). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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. Experimental studies have shown that this missense change affects SCN2A function (PMID: 11371648). -

not provided Uncertain:1
Mar 16, 2022
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Identified in an individual with epilepsy who inherited the variant from his father with febrile seizures in the published literature (Sugawara T et al., 2001; Ito et al., 2004), however, molecular analysis was limited to only sequencing of SCN2A; Functional studies demonstrate prolonged open state of the R187W mutant channel which may result in neuronal hyperexcitability (Sugawara T et al., 2001), however additional studies are needed to validate the functional effect of this variant in vivo; Also known as c.562C>T p.(Arg187Trp); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the intracellular loop between the S2 and S3 transmembrane segments of the first homologous domain; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24077912, 28191889, 15048894, 11371648, 15301839, 33004838) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.99
.;D;.;T;.;D;D;.;D
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.96
D;D;.;D;.;.;.;D;D
M_CAP
Pathogenic
0.56
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.2
.;H;H;.;H;H;H;H;.
PhyloP100
3.9
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-7.6
D;D;.;.;.;.;D;D;.
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D;.;.;.;.;D;D;.
Sift4G
Uncertain
0.014
D;D;.;.;D;.;D;D;D
Polyphen
1.0
.;D;D;.;D;D;D;D;.
Vest4
0.87, 0.91, 0.87, 0.87
MVP
1.0
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.93
gMVP
0.99
Mutation Taster
=1/99
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
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

Publications

Other links and lift over

dbSNP: rs121917748; hg19: chr2-166165261; COSMIC: COSV51847222; API