rs794726849

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate

The NM_001165963.4(SCN1A):​c.433A>G​(p.Met145Val) 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 (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SCN1A
NM_001165963.4 missense

Scores

14
4
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.93
Variant links:
Genes affected
SCN1A (HGNC:10585): (sodium voltage-gated channel alpha subunit 1) Voltage-dependent sodium channels are heteromeric complexes that regulate sodium exchange between intracellular and extracellular spaces and are essential for the generation and propagation of action potentials in muscle cells and neurons. Each sodium channel is composed of a large pore-forming, glycosylated alpha subunit and two smaller beta subunits. This gene encodes a sodium channel alpha subunit, which has four homologous domains, each of which contains six transmembrane regions. Allelic variants of this gene are associated with generalized epilepsy with febrile seizures and epileptic encephalopathy. Alternative splicing results in multiple transcript variants. The RefSeq Project has decided to create four representative RefSeq records. Three of the transcript variants are supported by experimental evidence and the fourth contains alternate 5' untranslated exons, the exact combination of which have not been experimentally confirmed for the full-length transcript. [provided by RefSeq, Oct 2015]
SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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), SCN1A. . Gene score misZ 5.2206 (greater than the threshold 3.09). Trascript score misZ 7.6022 (greater than threshold 3.09). GenCC has associacion of gene with migraine, familial hemiplegic, 3, familial hemiplegic migraine, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, myoclonic-astatic epilepsy, developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 6, familial or sporadic hemiplegic migraine, arthrogryposis, Lennox-Gastaut syndrome, generalized epilepsy with febrile seizures plus, type 2.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.907
PP5
Variant 2-166056451-T-C is Pathogenic according to our data. Variant chr2-166056451-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 190024.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN1ANM_001165963.4 linkuse as main transcriptc.433A>G p.Met145Val missense_variant 6/29 ENST00000674923.1 NP_001159435.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN1AENST00000674923.1 linkuse as main transcriptc.433A>G p.Met145Val missense_variant 6/29 NM_001165963.4 ENSP00000501589 P4P35498-1
SCN1A-AS1ENST00000651574.1 linkuse as main transcriptn.488-18837T>C intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
27
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:1
Pathogenic, criteria provided, single submitterresearchCenter for Bioinformatics, Peking UniversityDec 20, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
.;.;.;D;.;.;D;.;.;.
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D;D;D;D;.;D;.;.;D;D
M_CAP
Pathogenic
0.91
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.7
.;.;.;H;H;.;H;H;H;H
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-3.7
.;.;.;D;.;.;D;.;D;D
REVEL
Pathogenic
0.95
Sift
Uncertain
0.0010
.;.;.;D;.;.;D;.;D;D
Sift4G
Pathogenic
0.0010
.;.;.;D;.;.;D;.;D;D
Polyphen
0.92, 0.98
.;.;.;P;D;.;P;D;D;.
Vest4
0.87, 0.91, 0.85, 0.89
MutPred
0.56
Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);Loss of catalytic residue at M147 (P = 0.0347);
MVP
0.99
MPC
0.69
ClinPred
0.99
D
GERP RS
5.7
Varity_R
0.79
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs794726849; hg19: chr2-166912961; API