rs794726832

Variant names:

• chr2-165991976-CAAAAA-C
• rs794726832
• NM_001165963.4:c.5294_5298delTTTTT

Your query was ambiguous. Multiple possible variants found:

• chr2-165991976-CAAAAA-C
• chr2-165991976-CAAAAA-CAA
• chr2-165991976-CAAAAA-CAAA

Variant summary

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

The NM_001165963.4(SCN1A):​c.5294_5298delTTTTT​(p.Phe1765CysfsTer28) variant causes a frameshift change involving the alteration of a 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: 31)
• Consequence: SCN1A NM_001165963.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.26

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 12 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. There are 28 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-165991976-CAAAAA-C is Pathogenic according to our data. Variant chr2-165991976-CAAAAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 817682.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.5294_5298delTTTTT	p.Phe1765CysfsTer28	frameshift_variant	Exon 29 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.5294_5298delTTTTT	p.Phe1765CysfsTer28	frameshift_variant	Exon 29 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.5294_5298delTTTTT	p.Phe1765CysfsTer28	frameshift_variant	Exon 28 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.5261_5265delTTTTT	p.Phe1754CysfsTer28	frameshift_variant	Exon 26 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.5210_5214delTTTTT	p.Phe1737CysfsTer28	frameshift_variant	Exon 26 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

May 25, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5294_5298delTTTTT variant in the SCN1A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.5294_5298delTTTTT variant causes a frameshift starting with codon Phenylalanine, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 28 of the new reading frame, denoted p.Phe1765CysfsX28 . This variant is predicted to cause loss of normal protein function through protein truncation. The c.5294_5298delTTTTT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.5294_5298delTTTTT as a pathogenic variant. -

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: rs794726832; hg19: chr2-166848486;