chr2-166012262-A-AAT

Position:

• chr2-166012262-A-AAT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.3725_3726insAT​(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.15

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)

LOC102724058 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.3725_3726insAT	p.Asp1243LeufsTer28	frameshift_variant	22/29	ENST00000674923.1	NP_001159435.1
LOC102724058	NR_110598.1	n.176-3342_176-3341dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.3725_3726insAT	p.Asp1243LeufsTer28	frameshift_variant	22/29		NM_001165963.4	ENSP00000501589	P4
SCN1A-AS1	ENST00000651574.1	n.193-3342_193-3341dup		intron_variant, non_coding_transcript_variant

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2016	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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 206910). This variant is also known as p.I1242ins1270X. This premature translational stop signal has been observed in individual(s) with epilepsy (PMID: 17561957, 23195492). This variant is not present in population databases (gnomAD no frequency). 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). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs796053072; hg19: chr2-166868772;