rs1553541493

Positions:

• chr2-166038065-GAATTGC-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP3 BP3

The NM_001165963.4(SCN1A):​c.2651_2656delGCAATT​(p.Gly884_Ser886delinsAla) variant causes a disruptive 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a helix (size 11) in uniprot entity SCN1A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001165963.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP3: Nonframeshift variant in repetitive region in NM_001165963.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.2651_2656delGCAATT	p.Gly884_Ser886delinsAla	disruptive_inframe_deletion	18/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.2651_2656delGCAATT	p.Gly884_Ser886delinsAla	disruptive_inframe_deletion	18/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.2651_2656delGCAATT	p.Gly884_Ser886delinsAla	disruptive_inframe_deletion	17/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.2618_2623delGCAATT	p.Gly873_Ser875delinsAla	disruptive_inframe_deletion	15/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.2567_2572delGCAATT	p.Gly856_Ser858delinsAla	disruptive_inframe_deletion	15/26	5		ENSP00000386312.1

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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2021

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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: rs1553541493; hg19: chr2-166894575;