2-165996039-GT-GTT

Variant names:

• chr2-165996039-G-GT
• rs794726825
• NM_001165963.4:c.4554dupA

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.4554dupA​(p.Pro1519ThrfsTer18) 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: 32)
• Consequence: SCN1A NM_001165963.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.24

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 2-165996039-G-GT is Pathogenic according to our data. Variant chr2-165996039-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 206920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.4554dupA	p.Pro1519ThrfsTer18	frameshift_variant	Exon 27 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.4554dupA	p.Pro1519ThrfsTer18	frameshift_variant	Exon 27 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.4554dupA	p.Pro1519ThrfsTer18	frameshift_variant	Exon 26 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.4521dupA	p.Pro1508ThrfsTer18	frameshift_variant	Exon 24 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.4470dupA	p.Pro1491ThrfsTer18	frameshift_variant	Exon 24 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Seizure Pathogenic:2

Mar 25, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Migraine, familial hemiplegic, 3 Pathogenic:1

Sep 08, 2002

Center of Excellence for Medical Genomics, Chulalongkorn University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Pro1519Thrfs*18) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with SCN1A-related conditions (PMID: 17561957, 23195492, 31864146, 32090326). This variant is also known as c.4589insA (K1517ins1536X); c.4554-4555insA (P1519fsX1536). ClinVar contains an entry for this variant (Variation ID: 206920). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Dec 15, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.4554dupA: p.Pro1519ThrfsX18 (P1519TfsX18) in exon 24 of the SCN1A gene (NM_001165963.1). The normal sequence with the base that is duplicated in braces is: CGAAAAA{A}CCGC. The c.4554dupA mutation in the SCN1A gene was reported previously as c.4589insA using alternative nomenclature and was identified as a de novo mutation in an individual with Dravet syndrome (Marini et al., 2007). The duplication causes a frameshift starting with codon Proline 1519, changes this amino acid to a Threonine residue and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Pro1519ThrfsX18. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, the presence of c.4554dupA is consistent with a diagnosis of an SCN1A-related disorder. The variant is found in EPILEPSYV2-1 panel(s). -

Severe myoclonic epilepsy in infancy Pathogenic:1

Dec 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs794726825; hg19: chr2-166852549;