rs1553560831

Positions:

• chr2-166073495-CT-C
• chr2-166073495-CT-CTT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001165963.4(SCN1A):​c.126delA​(p.Asp43fs) 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN1A NM_001165963.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.658

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 Pathogenic. Variant got 12 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 2-166073495-CT-C is Pathogenic according to our data. Variant chr2-166073495-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 496115.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.126delA	p.Asp43fs	frameshift_variant	4/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.126delA	p.Asp43fs	frameshift_variant	4/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.126delA	p.Asp43fs	frameshift_variant	3/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.126delA	p.Asp43fs	frameshift_variant	1/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.126delA	p.Asp43fs	frameshift_variant	1/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 25, 2017

Variant summary: The SCN1A c.126delA (p.Asp43Metfs) variant results in a premature termination codon, predicted to cause a truncated or absent SCN1A protein due to nonsense mediated decay, which are commonly known mechanisms for disease ACMG, PVS1). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.664C>T/p.Arg222X; c.1561C>T/p.Gln521X). This variant has been reported in multiple SMEI patients. Another SCN1A variant, c.127delG (gives the same codon change as our variant of interest) was reported in a pt (De novo, age of onset at 6months) with classical Dravel syndrome (ACMG, PS1). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121410 control chromosomes (ACMG, PM2). Taken together, this variant is classified as Pathogenic. -

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: rs1553560831; hg19: chr2-166930005;