rs121917748

chr2-165308751-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PM1 PP2 PP3_Strong BS2

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. 12/21 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3 O:1
• Conservation: PhyloP100: 3.95

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.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001040142.2
• PP2: Missense variant where missense usually causes diseases, SCN2A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.562C>T	p.Arg188Trp	missense_variant	5/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.562C>T	p.Arg188Trp	missense_variant	5/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.562C>T	p.Arg188Trp	missense_variant	5/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.562C>T	p.Arg188Trp	missense_variant	5/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250874 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135694

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 SAS 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

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000160 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:1 Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Seizures, benign familial infantile, 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2004

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2021

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 07, 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. Experimental studies have shown that this missense change affects SCN2A function (PMID: 11371648). 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"). 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). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2022

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) -

Complex neurodevelopmental disorder Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

-

- -

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
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
MutationTaster	Benign	1.0	A;A;A;A
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

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

LitVar

Other links and lift over

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