NM_001040142.2:c.2960G>T

Variant names:

• chr2-165354232-G-T
• rs796053124
• NM_001040142.2:c.2960G>T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_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. 12/21 in silico tools predict a damaging 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:4
• Conservation: PhyloP100: 10.0

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 15 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 226) in uniprot entity SCN2A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 seizures, benign familial infantile, 3, Dravet syndrome, benign familial neonatal-infantile seizures, malignant migrating partial seizures of infancy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 11, developmental and epileptic encephalopathy, West syndrome, benign familial infantile epilepsy, episodic ataxia, type 9.
• 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 [Likely_pathogenic]. Clinvar id 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	c.2960G>T	p.Ser987Ile	missense_variant	Exon 17 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	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	Appris	UniProt
SCN2A	ENST00000375437.7	c.2960G>T	p.Ser987Ile	missense_variant	Exon 17 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.2960G>T	p.Ser987Ile	missense_variant	Exon 17 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.2960G>T	p.Ser987Ile	missense_variant	Exon 17 of 27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

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

- -

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

- -

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. -

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	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
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	D
LIST_S2	Uncertain	0.89	D;.;D;.;.;.;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;H;.;H;H;H;H
PrimateAI	Pathogenic	0.83	D
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
Polyphen		0.92	P;D;.;D;P;P;D
Vest4		0.77
MutPred		0.51		Loss of disorder (P = 0.0015);Loss of disorder (P = 0.0015);.;Loss of disorder (P = 0.0015);Loss of disorder (P = 0.0015);Loss of disorder (P = 0.0015);Loss of disorder (P = 0.0015);
MVP		0.98
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.95

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: rs796053124; hg19: chr2-166210742; COSMIC: COSV99332099;