rs1553519872

Positions:

• chr2-165991520-CA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001165963.4(SCN1A):​c.5754delT​(p.Ala1919fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.252

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0458 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-165991520-CA-C is Pathogenic according to our data. Variant chr2-165991520-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 530503.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.5754delT	p.Ala1919fs	frameshift_variant	29/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.5754delT	p.Ala1919fs	frameshift_variant	29/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.5754delT	p.Ala1919fs	frameshift_variant	28/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.5721delT	p.Ala1908fs	frameshift_variant	26/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.5670delT	p.Ala1891fs	frameshift_variant	26/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2017

This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the SCN1A gene (p.Ala1919Leufs*13). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 91 amino acids of the SCN1A protein. This variant has not been reported in the literature in individuals with SCN1A-related disease. This variant has been observed as de novo in an individual with febrile seizures (Invite). For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Arg1924Leufs*8) that lies downstream of this variant has been determined to be pathogenic (PMID: 27465585). This suggests that deletion of this region of the SCN1A protein is causative of disease. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1553519872; hg19: chr2-166848030;