2-165991547-AAGT-A

Variant names:

• chr2-165991547-AAGT-A
• rs1553519902
• NM_001165963.4:c.5725_5727delACT

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.5725_5727delACT​(p.Thr1909del) variant causes a conservative inframe deletion 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0
• Publications: 0 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 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_001165963.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001165963.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-165991547-AAGT-A is Pathogenic according to our data. Variant chr2-165991547-AAGT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 530525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.5725_5727delACT	p.Thr1909del	conservative_inframe_deletion	Exon 29 of 29	NP_001159435.1
	SCN1A	NM_001202435.3		c.5725_5727delACT	p.Thr1909del	conservative_inframe_deletion	Exon 28 of 28	NP_001189364.1
	SCN1A	NM_001353948.2		c.5725_5727delACT	p.Thr1909del	conservative_inframe_deletion	Exon 27 of 27	NP_001340877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.5725_5727delACT	p.Thr1909del	conservative_inframe_deletion	Exon 29 of 29	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.5725_5727delACT	p.Thr1909del	conservative_inframe_deletion	Exon 28 of 28	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.5692_5694delACT	p.Thr1898del	conservative_inframe_deletion	Exon 26 of 26	ENSP00000364554.3

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy Pathogenic:1

Aug 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.5725_5727del, results in the deletion of 1 amino acid(s) of the SCN1A protein (p.Thr1909del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with severe myoclonic epilepsy of infancy syndrome and/or generalized epilepsy (PMID: 21248271, 28102150). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 530525). This variant disrupts the p.Thr1909 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12083760, 17054685, 28202706). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:1

Aug 07, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); This deletion is predicted to be within the C-terminal cytoplasmic domain; In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; This variant is associated with the following publications: (PMID: 28102150, 32090326, 21248271)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=48/52	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: rs1553519902; hg19: chr2-166848057;