rs200138205

chr2-165365200-G-Achr2-165365200-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP6 BS1 BS2

The NM_001040142.2(SCN2A):c.3457G>A(p.Glu1153Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,613,778 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1153Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:5
• Conservation: PhyloP100: 8.02

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 Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SCN2A
• BP6: Variant 2-165365200-G-A is Benign according to our data. Variant chr2-165365200-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206987.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=3, Benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000184 (28/152102) while in subpopulation NFE AF= 0.000368 (25/68016). AF 95% confidence interval is 0.000255. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.3457G>A	p.Glu1153Lys	missense_variant	18/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.3457G>A	p.Glu1153Lys	missense_variant	18/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.3457G>A	p.Glu1153Lys	missense_variant	18/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.3457G>A	p.Glu1153Lys	missense_variant	18/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 251444 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000387 AC: 566 AN: 1461676 Hom.: 1 Cov.: 32 AF XY: 0.000371 AC XY: 270 AN XY: 727142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000472

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74314

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000266 Hom.: 0

Bravo AF: 0.000200

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000600

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	SCN2A: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 28, 2016	- -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 02, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1153 of the SCN2A protein (p.Glu1153Lys). This variant is present in population databases (rs200138205, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Rolandic epilepsy (PMID: 29358611). ClinVar contains an entry for this variant (Variation ID: 206987). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2017	- -

Childhood epilepsy with centrotemporal spikes Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Developmental and epileptic encephalopathy, 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 14, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11;C5394520:Episodic ataxia, type 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

SCN2A NM_021007.2 exon 18 p.Glu1153Lys (c.3457G>A): This variant has not been reported in the literature but is present in 39/126674 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/dbsnp/rs200138205). This variant is present in ClinVar (Variation ID: 206987). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 28, 2017

- -

SCN2A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Seizures, benign familial infantile, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D;.;T;.;D;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;D;.;.;.;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.2	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.8	D;.;.;.;.;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0030	D;.;.;.;.;D;D
Sift4G	Uncertain	0.034	D;.;.;D;.;D;D
Polyphen		0.94	P;P;.;P;P;P;P
Vest4		0.31
MVP		0.85
ClinPred		0.31	T
GERP RS		5.8
Varity_R		0.48
gMVP		0.65

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: rs200138205; hg19: chr2-166221710; COSMIC: COSV51838476;