2-165314005-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP2PP3

The NM_001040142.2(SCN2A):​c.1280C>T​(p.Ala427Val) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A427D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SCN2A
NM_001040142.2 missense

Scores

16
2
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
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 Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr2-165314005-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130212.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Uncertain_significance=1, Pathogenic=1}.
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, 0.811

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN2ANM_001040142.2 linkc.1280C>T p.Ala427Val missense_variant Exon 10 of 27 ENST00000375437.7 NP_001035232.1 Q99250-1
SCN2ANM_001371246.1 linkc.1280C>T p.Ala427Val missense_variant Exon 10 of 27 ENST00000631182.3 NP_001358175.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN2AENST00000375437.7 linkc.1280C>T p.Ala427Val missense_variant Exon 10 of 27 5 NM_001040142.2 ENSP00000364586.2 Q99250-1
SCN2AENST00000631182.3 linkc.1280C>T p.Ala427Val missense_variant Exon 10 of 27 5 NM_001371246.1 ENSP00000486885.1 Q99250-2
SCN2AENST00000283256.10 linkc.1280C>T p.Ala427Val missense_variant Exon 10 of 27 1 ENSP00000283256.6 Q99250-1
SCN2AENST00000424833.5 linkc.1280C>T p.Ala427Val missense_variant Exon 10 of 11 1 ENSP00000406454.2 F6U291

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Uncertain:1
Oct 18, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 427 of the SCN2A protein (p.Ala427Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.96
.;D;.;T;.;D;D;.
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;.;D;.;.;.;D
M_CAP
Pathogenic
0.60
D
MetaRNN
Pathogenic
0.81
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.2
.;M;M;.;M;M;M;M
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-3.8
D;D;.;.;.;.;D;D
REVEL
Pathogenic
0.78
Sift
Pathogenic
0.0
D;D;.;.;.;.;D;D
Sift4G
Pathogenic
0.0010
D;D;.;.;D;.;D;D
Polyphen
1.0, 1.0
.;D;D;.;D;D;D;D
Vest4
0.73, 0.72, 0.73, 0.73
MutPred
0.40
Loss of disorder (P = 0.0883);Loss of disorder (P = 0.0883);Loss of disorder (P = 0.0883);.;Loss of disorder (P = 0.0883);Loss of disorder (P = 0.0883);Loss of disorder (P = 0.0883);Loss of disorder (P = 0.0883);
MVP
0.97
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.86
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-166170515; COSMIC: COSV105105080; COSMIC: COSV105105080; API