rs796053178

Positions:

• chr2-165313732-C-G
• chr2-165313732-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001040142.2(SCN2A):​c.1147C>G​(p.Gln383Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q383L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001040142.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-165313733-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1514630.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, SCN2A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 2-165313732-C-G is Pathogenic according to our data. Variant chr2-165313732-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 207050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.1147C>G	p.Gln383Glu	missense_variant	9/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.1147C>G	p.Gln383Glu	missense_variant	9/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.1147C>G	p.Gln383Glu	missense_variant	9/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.1147C>G	p.Gln383Glu	missense_variant	9/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 16, 2017

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in the literature in an individual with Ohtahara syndrome and a sibling affected with benign familial neonatal-infantile seizures inherited from an obligate carrier father affected with infantile epilepsy and intellectual disability (PMID: 27781028). In addition, family studies have indicated that this variant was not present in the parents of an individual with early-onset epilepsy, which suggests that it was de novo in that affected individual (Invitae). ClinVar contains an entry for this variant (Variation ID: 207050). This variant is not present in population databases (rs796053178, ExAC no frequency). This sequence change replaces glutamine with glutamic acid at codon 383 of the SCN2A protein (p.Gln383Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2013

p.Gln383Glu (CAA>GAA): c.1147 C>G in exon 9 of the SCN2A gene (NM_021007.2). The Gln383Glu missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or among the various ethnic groups studied in the 1000 Genomes Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative as an uncharged Glutamine residue is replaced by a negatively charged Glutamic acid residue. Gln383Glu alters a conserved position between the S5 and S6 segments of the first transmembrane domain of the protein and several in-silico algorithms predict it may be damaging to the structure/function of the protein. This variant has been observed de novo without verified parentage. The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.;D;.;.;.;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	D;D;.;.;.;.;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;.;.;.;.;D;D
Sift4G	Pathogenic	0.0010	D;D;.;.;D;.;D;D
Polyphen		0.99, 0.99	.;D;D;.;D;D;D;D
Vest4		0.91, 0.94, 0.91
MutPred		0.75		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);.;Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP		1.0
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.82
gMVP		0.99

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: rs796053178; hg19: chr2-166170242;