rs1553463466

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_001040142.2(SCN2A):​c.4996C>T​(p.Leu1666Phe) 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SCN2A
NM_001040142.2 missense

Scores

13
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 2.06
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 7 ACMG points.

PM1
In a repeat IV (size 298) in uniprot entity SCN2A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_001040142.2
PM2
Very rare variant in population databases, with high coverage;
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, 0.908

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN2ANM_001040142.2 linkuse as main transcriptc.4996C>T p.Leu1666Phe missense_variant 27/27 ENST00000375437.7 NP_001035232.1
SCN2ANM_001371246.1 linkuse as main transcriptc.4996C>T p.Leu1666Phe missense_variant 27/27 ENST00000631182.3 NP_001358175.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN2AENST00000375437.7 linkuse as main transcriptc.4996C>T p.Leu1666Phe missense_variant 27/275 NM_001040142.2 ENSP00000364586 P1Q99250-1
SCN2AENST00000631182.3 linkuse as main transcriptc.4996C>T p.Leu1666Phe missense_variant 27/275 NM_001371246.1 ENSP00000486885 Q99250-2

Frequencies

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

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 09, 2015- -
Complex neurodevelopmental disorder Uncertain:1
Uncertain significance, no assertion criteria providedprovider interpretationGenomeConnect - Simons SearchlightJan 29, 2019Submission 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 2015-11-09 by GTR ID of laboratory name 61756. The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.39
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.96
D;.;T;.;D;D;.
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.91
D;.;D;.;.;.;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.1
H;H;.;H;H;H;H
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Uncertain
-3.5
D;.;.;.;.;D;D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0010
D;.;.;.;.;D;D
Sift4G
Pathogenic
0.0010
D;.;.;D;.;D;D
Polyphen
1.0
D;D;.;D;D;D;D
Vest4
0.74
MutPred
0.72
Loss of stability (P = 0.1662);Loss of stability (P = 0.1662);.;Loss of stability (P = 0.1662);Loss of stability (P = 0.1662);Loss of stability (P = 0.1662);Loss of stability (P = 0.1662);
MVP
0.99
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.92
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: rs1553463466; hg19: chr2-166245312; API