2-165090160-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_006922.4(SCN3A):​c.5993A>G​(p.Asn1998Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SCN3A
NM_006922.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.552
Variant links:
Genes affected
SCN3A (HGNC:10590): (sodium voltage-gated channel alpha subunit 3) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is found in a cluster of five alpha subunit genes on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN3A. . Gene score misZ 4.618 (greater than the threshold 3.09). Trascript score misZ 6.3553 (greater than threshold 3.09). GenCC has associacion of gene with undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy, epilepsy, familial focal, with variable foci 4, developmental and epileptic encephalopathy, 62.
BP4
Computational evidence support a benign effect (MetaRNN=0.052068442).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN3ANM_006922.4 linkuse as main transcriptc.5993A>G p.Asn1998Ser missense_variant 28/28 ENST00000283254.12 NP_008853.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN3AENST00000283254.12 linkuse as main transcriptc.5993A>G p.Asn1998Ser missense_variant 28/281 NM_006922.4 ENSP00000283254 P1Q9NY46-3
ENST00000638199.1 linkuse as main transcriptn.1144-960T>C intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 06, 2021In 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SCN3A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 1998 of the SCN3A protein (p.Asn1998Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
16
DANN
Benign
0.87
DEOGEN2
Benign
0.26
T;.;.;.
Eigen
Benign
-0.60
Eigen_PC
Benign
-0.32
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.65
T;T;T;T
M_CAP
Benign
0.058
D
MetaRNN
Benign
0.052
T;T;T;T
MetaSVM
Benign
-0.40
T
MutationAssessor
Benign
-0.90
N;N;.;.
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-0.21
N;N;.;N
REVEL
Benign
0.28
Sift
Benign
1.0
T;T;.;T
Sift4G
Benign
0.79
T;T;.;T
Polyphen
0.0
.;B;.;B
Vest4
0.051
MutPred
0.26
Gain of phosphorylation at N1998 (P = 2e-04);Gain of phosphorylation at N1998 (P = 2e-04);.;.;
MVP
0.30
MPC
0.54
ClinPred
0.054
T
GERP RS
4.9
Varity_R
0.046
gMVP
0.19

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: chr2-165946670; API