rs1553463718
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_ModeratePP5_Moderate
The NM_001040142.2(SCN2A):c.5551C>T(p.Arg1851Trp) 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 pathogenic 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
NM_001040142.2 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 0.757
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 9 ACMG points.
PM1
?
In a hotspot region, there are 2 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;
PP2
?
Missense variant where missense usually causes diseases, SCN2A
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.897
PP5
?
Variant 2-165389357-C-T is Pathogenic according to our data. Variant chr2-165389357-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495262.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.5551C>T | p.Arg1851Trp | missense_variant | 27/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.5551C>T | p.Arg1851Trp | missense_variant | 27/27 | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.5551C>T | p.Arg1851Trp | missense_variant | 27/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.5551C>T | p.Arg1851Trp | missense_variant | 27/27 | 5 | NM_001371246.1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Seizures, benign familial infantile, 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | NeuroMeGen, Hospital Clinico Santiago de Compostela | Jan 01, 2018 | - - |
Complex neurodevelopmental disorder Uncertain:1
Uncertain significance, no assertion criteria provided | provider interpretation | GenomeConnect - Simons Searchlight | Jan 29, 2019 | Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-01-29 and interpreted as Variant of Uncertain significance. Variant was initially reported on 2017-09-25. The reporting laboratory might also submit to ClinVar. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Pathogenic
D;.;T;.;D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;.;D;.;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.;H;H;H;H
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;.;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;.;.;D;D
Sift4G
Pathogenic
D;.;.;D;.;D;D
Polyphen
D;D;.;D;D;D;D
Vest4
MutPred
Gain of glycosylation at S1848 (P = 0.1051);Gain of glycosylation at S1848 (P = 0.1051);.;Gain of glycosylation at S1848 (P = 0.1051);Gain of glycosylation at S1848 (P = 0.1051);Gain of glycosylation at S1848 (P = 0.1051);Gain of glycosylation at S1848 (P = 0.1051);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at