2-165342465-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_001040142.2(SCN2A):​c.2558G>C​(p.Arg853Pro) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R853Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SCN2A
NM_001040142.2 missense

Scores

16
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 10.0
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1
In a repeat II (size 272) in uniprot entity SCN2A_HUMAN there are 22 pathogenic changes around while only 1 benign (96%) 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 chr2-165342465-G-A is described in Lovd as [Likely_pathogenic].
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, 0.986
PP5
Variant 2-165342465-G-C is Pathogenic according to our data. Variant chr2-165342465-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1451854.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN2ANM_001040142.2 linkc.2558G>C p.Arg853Pro missense_variant Exon 15 of 27 ENST00000375437.7 NP_001035232.1 Q99250-1
SCN2ANM_001371246.1 linkc.2558G>C p.Arg853Pro missense_variant Exon 15 of 27 ENST00000631182.3 NP_001358175.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN2AENST00000375437.7 linkc.2558G>C p.Arg853Pro missense_variant Exon 15 of 27 5 NM_001040142.2 ENSP00000364586.2 Q99250-1
SCN2AENST00000631182.3 linkc.2558G>C p.Arg853Pro missense_variant Exon 15 of 27 5 NM_001371246.1 ENSP00000486885.1 Q99250-2
SCN2AENST00000283256.10 linkc.2558G>C p.Arg853Pro missense_variant Exon 15 of 27 1 ENSP00000283256.6 Q99250-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Pathogenic:1
Nov 22, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense change has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (Invitae). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg853 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23935176, 25772804, 28379373, 29186148). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt SCN2A protein function. ClinVar contains an entry for this variant (Variation ID: 1451854). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 853 of the SCN2A protein (p.Arg853Pro). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D;.;T;.;D;D;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.97
D;.;D;.;.;.;D
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.6
H;H;.;H;H;H;H
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-6.4
D;.;.;.;.;D;D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;.;.;.;.;D;D
Sift4G
Uncertain
0.022
D;.;.;D;.;D;D
Polyphen
1.0
D;D;.;D;D;D;D
Vest4
0.98
MutPred
0.88
Loss of MoRF binding (P = 0.0023);Loss of MoRF binding (P = 0.0023);.;Loss of MoRF binding (P = 0.0023);Loss of MoRF binding (P = 0.0023);Loss of MoRF binding (P = 0.0023);Loss of MoRF binding (P = 0.0023);
MVP
1.0
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.98
gMVP
1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-166198975; API