rs796053129

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Moderate

The NM_001040142.2(SCN2A):​c.3944G>A​(p.Arg1315Lys) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1315S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SCN2A
NM_001040142.2 missense

Scores

13
5
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 11 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, 5 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 chr2-165373320-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1708035.Status of the report is no_assertion_criteria_provided, 0 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN2A. . Trascript score misZ 8.7114 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.884
PP5
Variant 2-165373319-G-A is Pathogenic according to our data. Variant chr2-165373319-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 206990.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-165373319-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN2ANM_001040142.2 linkuse as main transcriptc.3944G>A p.Arg1315Lys missense_variant 21/27 ENST00000375437.7
SCN2ANM_001371246.1 linkuse as main transcriptc.3944G>A p.Arg1315Lys missense_variant 21/27 ENST00000631182.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN2AENST00000375437.7 linkuse as main transcriptc.3944G>A p.Arg1315Lys missense_variant 21/275 NM_001040142.2 P1Q99250-1
SCN2AENST00000631182.3 linkuse as main transcriptc.3944G>A p.Arg1315Lys missense_variant 21/275 NM_001371246.1 Q99250-2

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

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxOct 23, 2013p.Arg1315Lys (AGA>AAA): c.3944 G>A in exon 21 of the SCN2A gene (NM_021007.2). The Arg1315Lys missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a conservative substitution of one positively charged amino acid for another. However, it alters a highly conserved position in the S4 segment of the third transmembrane domain and other missense mutations associated with epilepsy have been reported in this region of the protein. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. This variant has been observed de novo without verified parentage. The variant is found in INFANT-EPI panel(s). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.46
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
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
0.37
D
MetaRNN
Pathogenic
0.88
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.0
M;M;.;M;M;M;M
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Uncertain
-2.6
D;.;.;.;.;D;D
REVEL
Pathogenic
0.80
Sift
Uncertain
0.0080
D;.;.;.;.;D;D
Sift4G
Uncertain
0.0090
D;.;.;D;.;D;D
Polyphen
0.99
D;D;.;D;D;D;D
Vest4
0.88
MutPred
0.68
Loss of methylation at R1315 (P = 0.009);Loss of methylation at R1315 (P = 0.009);.;Loss of methylation at R1315 (P = 0.009);Loss of methylation at R1315 (P = 0.009);Loss of methylation at R1315 (P = 0.009);Loss of methylation at R1315 (P = 0.009);
MVP
0.99
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.94
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs796053129; hg19: chr2-166229829; API