rs590478

Positions:

• chr2-166123379-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001165963.4(SCN1A):​c.-142+3545A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 152,114 control chromosomes in the GnomAD database, including 3,664 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3664 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.212

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)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.-142+3545A>G		intron_variant		ENST00000674923.1	NP_001159435.1
SCN1A-AS1	NR_110260.1	n.259+30716T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.-142+3545A>G		intron_variant			NM_001165963.4	ENSP00000501589	P4
SCN1A-AS1	ENST00000651574.1	n.937+19031T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30067 AN: 151996 Hom.: 3661 Cov.: 32

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.199

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

Gnomad4 AMR exome AF: 0.500

GnomAD4 genome AF: 0.198 AC: 30078 AN: 152112 Hom.: 3664 Cov.: 32 AF XY: 0.202 AC XY: 14987 AN XY: 74376

Gnomad4 AFR AF: 0.0612

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.366

Gnomad4 SAS AF: 0.259

Gnomad4 FIN AF: 0.270

Gnomad4 NFE AF: 0.244

Gnomad4 OTH AF: 0.199

Alfa AF: 0.205 Hom.: 426

Bravo AF: 0.192

Asia WGS AF: 0.272 AC: 946 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.3
DANN	Benign	0.59

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs590478; hg19: chr2-166979889;