rs387906684

Variant names:

• chr2-165367327-G-A
• rs387906684
• NM_001040142.2:c.3631G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-165367327-G-A
• chr2-165367327-G-T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001040142.2(SCN2A):​c.3631G>A​(p.Glu1211Lys) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 10.0
• Publications: 33 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 17 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, 7 uncertain in NM_001040142.2
• 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 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, 0.979
• PP5: Variant 2-165367327-G-A is Pathogenic according to our data. Variant chr2-165367327-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 29886.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	c.3631G>A	p.Glu1211Lys	missense_variant	Exon 19 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.3631G>A	p.Glu1211Lys	missense_variant	Exon 19 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.3631G>A	p.Glu1211Lys	missense_variant	Exon 19 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.3631G>A	p.Glu1211Lys	missense_variant	Exon 19 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.3631G>A	p.Glu1211Lys	missense_variant	Exon 19 of 27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 11 Pathogenic:4

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The amino acid Glu at position 1211 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported in individuals with clinical features of early infantile epileptic encephalopathy (Ogiwara et al, 2009, Lee et al, 2014). Experimental studies have shown that this missense change significantly changed the functional property of the sodium channels leading to both augmented and reduced channel activities by electrophysiological analyses in the cells (Ogiwara et al, 2009). The p.Glu1211Lys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Glu1211Lys in SCN2A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Sep 29, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 16, 2013

UCLA Clinical Genomics Center, UCLA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PP3, PP5 -

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

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4_Supporting+PS2+PP4+PP3_Moderate+PP2 -

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

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1211 of the SCN2A protein (p.Glu1211Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 19786696, 25326637, 25459969, 28379373). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 29886). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN2A protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN2A function (PMID: 19786696). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jul 24, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect and suggest that this variant alters the channel activity of the SCN2A protein (PMID: 19786696, 37578743); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This substitution is predicted to be within the transmembrane segment S1 of the third homologous domain; This variant is associated with the following publications: (PMID: 19786696, 28379373, 29655203, 32090326, 33057194, 25459969, 32651551, 35431799, 36084525, 37329172, 35982159, 31440721, 37578743, 34489640) -

Seizures, benign familial infantile, 3 Pathogenic:1

May 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

West syndrome Pathogenic:1

Feb 16, 2022

Neurology Department, Shenzhen Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.;T;.;D;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;.;.;.;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;M;.;M;M;M;M
PhyloP100		10
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.8	D;.;.;.;.;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;.;.;.;.;D;D
Sift4G	Uncertain	0.057	T;.;.;T;.;T;T
Polyphen		0.99	D;D;.;D;D;D;D
Vest4		0.87
MutPred		0.90		Gain of methylation at E1211 (P = 0.0024);Gain of methylation at E1211 (P = 0.0024);.;Gain of methylation at E1211 (P = 0.0024);Gain of methylation at E1211 (P = 0.0024);Gain of methylation at E1211 (P = 0.0024);Gain of methylation at E1211 (P = 0.0024);
MVP		0.99
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.93
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906684; hg19: chr2-166223837; COSMIC: COSV99330257;