rs397514459

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.2584C>T​(p.Arg862*) variant causes a stop gained 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SCN1A
NM_001165963.4 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.700
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-166039428-G-A is Pathogenic according to our data. Variant chr2-166039428-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166039428-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN1ANM_001165963.4 linkuse as main transcriptc.2584C>T p.Arg862* stop_gained 17/29 ENST00000674923.1 NP_001159435.1 P35498-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN1AENST00000674923.1 linkuse as main transcriptc.2584C>T p.Arg862* stop_gained 17/29 NM_001165963.4 ENSP00000501589.1 P35498-1
SCN1AENST00000303395.9 linkuse as main transcriptc.2584C>T p.Arg862* stop_gained 16/285 ENSP00000303540.4 P35498-1
SCN1AENST00000375405.7 linkuse as main transcriptc.2551C>T p.Arg851* stop_gained 14/265 ENSP00000364554.3 P35498-2
SCN1AENST00000409050.1 linkuse as main transcriptc.2500C>T p.Arg834* stop_gained 14/265 ENSP00000386312.1 P35498-3

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1405258
Hom.:
0
Cov.:
36
AF XY:
0.00
AC XY:
0
AN XY:
701242
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJul 21, 2021PM2, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2020- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 19, 2014- -
Pathogenic, no assertion criteria providedclinical testingGenetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen HealthcareApr 23, 2023- -
Severe myoclonic epilepsy in infancy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The stop gained p.R862* in SCN1A (NM_001165963.4) has been reported previously in individuals affected with Idiopathic childhood epilepsies (Orrico et al, 2009). The p.R862* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. The p.R862* variant is a loss of function variant in the gene SCN1A, which is intolerant of Loss of Function variants. The nucleotide change in SCN1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterresearchCenter for Bioinformatics, Peking UniversityDec 20, 2014- -
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 02, 2023This sequence change creates a premature translational stop signal (p.Arg862*) in the SCN1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with SCN1A-related conditions (PMID: 19522081, 29056246). ClinVar contains an entry for this variant (Variation ID: 189857). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
38
DANN
Uncertain
1.0
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.92
D
Vest4
0.97
GERP RS
2.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs397514459; hg19: chr2-166895938; COSMIC: COSV57665384; COSMIC: COSV57665384; API