2-165354232-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_001040142.2(SCN2A):c.2960G>T(p.Ser987Ile) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S987C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SCN2A
NM_001040142.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 10.0

Publications

10 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

SCN2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr2-165354231-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1502099.Status of the report is criteria_provided_single_submitter, 1 stars.

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, 0.9

PP5

Variant 2-165354232-G-T is Pathogenic according to our data. Variant chr2-165354232-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 206978.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 link	c.2960G>T	p.Ser987Ile	missense_variant	Exon 17 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1 link	c.2960G>T	p.Ser987Ile	missense_variant	Exon 17 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SCN2A	ENST00000375437.7 link	c.2960G>T	p.Ser987Ile	missense_variant	Exon 17 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3 link	c.2960G>T	p.Ser987Ile	missense_variant	Exon 17 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10 link	c.2960G>T	p.Ser987Ile	missense_variant	Exon 17 of 27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 11

Pathogenic:1

Jan 22, 2013

UCLA Clinical Genomics Center, UCLA

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Pathogenic:1

Feb 05, 2018

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S987I variant (also known as c.2960G>T), located in coding exon 16 of the SCN2A gene, results from a G to T substitution at nucleotide position 2960. The serine at codon 987 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration has been detected as a de novo occurrence in an individual with early infantile epileptic encephalopathy (EIEE) (Trump N et al. J. Med. Genet., 2016 May;53:310-7) and was also detected in an individual with epilepsy, vertigo, and episodic ataxia (Fokstuen S et al. Hum. Genomics, 2016 Jun;10:24). In addition, this variant lies buried a domain and is more disruptive than known nearby pathogenic variants (Ambry internal data; Berman HM; Acta Crystallogr. D Biol. Crystallogr. 2002 Jun;58). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Seizure;C0042571:Vertigo;C1720189:Hereditary episodic ataxia

Pathogenic:1

Nov 04, 2015

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:1

Apr 01, 2016

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Ser987Ile missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Ser987Ile in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a polar Serine residue is replaced by a non-polar Isoleucine residue. The Ser987Ile substitution alters a highly conserved position in the intracellular loop between the second and third transmembrane domains, and other mutations in this region of the protein have been reported in association with benign familial neonatal-infantile seizures (Shi et al., 2012). Additionally, several in silico algorithms predict Ser987Ile is damaging to protein structure/function. Therefore, Ser987Ile is a strong candidate for a disease-causing mutation. The variant is found in EPILEPSY,INFANT-EPI panel(s).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.;T;.;D;D;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;.;D;.;.;.;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.90

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;H;.;H;H;H;H

PhyloP100

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.7

D;.;.;.;.;D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;.;.;.;.;D;D

Sift4G

Uncertain

0.021

D;.;.;D;.;D;D

Vest4

0.77

ClinPred

1.0

GERP RS

4.8

Varity_R

0.94

gMVP

0.95

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over