2-165994176-CAA-CA

Variant names:

• chr2-165994176-CA-C
• rs796053083
• NM_001165963.4:c.4821delT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001165963.4(SCN1A):​c.4821delT​(p.Phe1607LeufsTer11) variant causes a frameshift change. 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: 3.81
• Publications: 1 publications found

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

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 416 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-165994176-CA-C is Pathogenic according to our data. Variant chr2-165994176-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 206921.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165963.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	NM_001165963.4	MANE Select	c.4821delT	p.Phe1607LeufsTer11	frameshift	Exon 28 of 29	NP_001159435.1
	SCN1A	NM_001202435.3		c.4821delT	p.Phe1607LeufsTer11	frameshift	Exon 27 of 28	NP_001189364.1
	SCN1A	NM_001353948.2		c.4821delT	p.Phe1607LeufsTer11	frameshift	Exon 26 of 27	NP_001340877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.4821delT	p.Phe1607LeufsTer11	frameshift	Exon 28 of 29	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.4821delT	p.Phe1607LeufsTer11	frameshift	Exon 27 of 28	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.4788delT	p.Phe1596LeufsTer11	frameshift	Exon 25 of 26	ENSP00000364554.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 30, 2013

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.4821delT: p.Phe1607LeufsX11 (F1607LfsX11) in exon 25 of the SCN1A gene (NM_001165963.1). The normal sequence with the bases that are deleted in braces is: TATTTT{T}GATTTTG. The c.4821delT mutation in the SCN1A gene causes a frameshift starting with codon Phenylalanine 1607, changes this amino acid to a Leucine residue and creates a Stop codon at position 11 of the new reading frame, denoted p.Phe1607LeufsX11. This mutation is predicted to cause loss of normal protein function through protein truncation. Although this mutation has not been previously reported to our knowledge, many other frameshift mutations have been reported in the SCN1A gene in association with epilepsy. Therefore, the presence of c.4821delT is consistent with a diagnosis of an SCN1A-related disorder. The variant is found in EPILEPSY panel(s).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs796053083; hg19: chr2-166850686;