rs796053072

Variant summary

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

The NM_001165963.4(SCN1A):​c.3724_3725dupAT​(p.Asp1243LeufsTer28) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I1242I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SCN1A
NM_001165963.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.15
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 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 2-166012262-A-AAT is Pathogenic according to our data. Variant chr2-166012262-A-AAT is described in ClinVar as [Pathogenic]. Clinvar id is 206910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN1ANM_001165963.4 linkc.3724_3725dupAT p.Asp1243LeufsTer28 frameshift_variant Exon 22 of 29 ENST00000674923.1 NP_001159435.1 P35498-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN1AENST00000674923.1 linkc.3724_3725dupAT p.Asp1243LeufsTer28 frameshift_variant Exon 22 of 29 NM_001165963.4 ENSP00000501589.1 P35498-1
SCN1AENST00000303395.9 linkc.3724_3725dupAT p.Asp1243LeufsTer28 frameshift_variant Exon 21 of 28 5 ENSP00000303540.4 P35498-1
SCN1AENST00000375405.7 linkc.3691_3692dupAT p.Asp1232LeufsTer28 frameshift_variant Exon 19 of 26 5 ENSP00000364554.3 P35498-2
SCN1AENST00000409050.1 linkc.3640_3641dupAT p.Asp1215LeufsTer28 frameshift_variant Exon 19 of 26 5 ENSP00000386312.1 P35498-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1457306
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
725026
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.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Jun 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 01, 2016
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

c.3724_3725dupAT: p.Asp1243LeufsX28 (D1243LfsX28) in exon 19 of the SCN1A gene (NM_001165963.1). The normal sequence with the bases that are duplicated in bases is TATAT{dupAT}TGAT. The c.3724_3725dupAT pathogenic variant in the SCN1A gene has been reported previously, using alternate nomenclature, as a de novo mutation in an individual with myoclonic epilepsy in infancy (Marini et al., 2007) and in another individual with intractable epilepsy in which the inheritance pattern was unknown (Wang et al., 2012). The c.3724_3725dupAT pathogenic variant causes a frameshift starting with codon Aspartic acid 1243, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 28 of the new reading frame, denoted p.Asp1243LeufsX28. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The presence of c.3724_3725dupAT is consistent with a diagnosis of an SCN1A-related disorder. The variant is found in EPILEPSY panel(s). -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Sep 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asp1243Leufs*28) 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 epilepsy (PMID: 17561957, 23195492). This variant is also known as p.I1242ins1270X. ClinVar contains an entry for this variant (Variation ID: 206910). For these reasons, this variant has been classified as Pathogenic. -

Developmental and epileptic encephalopathy 6B Pathogenic:1
Dec 03, 2023
3billion
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000206910 /PMID: 17561957). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs796053072; hg19: chr2-166868772; API