rs1542484

Positions:

• chr2-166048865-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001165963.4(SCN1A):​c.1028+21T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 1,484,396 control chromosomes in the GnomAD database, including 206,796 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18620 hom., cov: 31)
  • Exomes 𝑓: 0.53 (188176 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.295

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-166048865-A-G is Benign according to our data. Variant chr2-166048865-A-G is described in ClinVar as [Benign]. Clinvar id is 496114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.1028+21T>C		intron_variant		ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.1028+21T>C		intron_variant			NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.487+12735A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.487 AC: 73828 AN: 151622 Hom.: 18617 Cov.: 31

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.583

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.556

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.544

Gnomad OTH AF: 0.483

GnomAD3 exomes AF: 0.524 AC: 130644 AN: 249178 Hom.: 34610 AF XY: 0.528 AC XY: 71095 AN XY: 134714

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.502

Gnomad ASJ exome AF: 0.539

Gnomad EAS exome AF: 0.576

Gnomad SAS exome AF: 0.553

Gnomad FIN exome AF: 0.535

Gnomad NFE exome AF: 0.537

Gnomad OTH exome AF: 0.514

GnomAD4 exome AF: 0.528 AC: 704300 AN: 1332654 Hom.: 188176 Cov.: 21 AF XY: 0.530 AC XY: 355155 AN XY: 670414

Gnomad4 AFR exome AF: 0.332

Gnomad4 AMR exome AF: 0.505

Gnomad4 ASJ exome AF: 0.539

Gnomad4 EAS exome AF: 0.554

Gnomad4 SAS exome AF: 0.546

Gnomad4 FIN exome AF: 0.537

Gnomad4 NFE exome AF: 0.534

Gnomad4 OTH exome AF: 0.519

GnomAD4 genome AF: 0.487 AC: 73852 AN: 151742 Hom.: 18620 Cov.: 31 AF XY: 0.488 AC XY: 36195 AN XY: 74122

Gnomad4 AFR AF: 0.349

Gnomad4 AMR AF: 0.508

Gnomad4 ASJ AF: 0.540

Gnomad4 EAS AF: 0.557

Gnomad4 SAS AF: 0.556

Gnomad4 FIN AF: 0.536

Gnomad4 NFE AF: 0.544

Gnomad4 OTH AF: 0.486

Alfa AF: 0.522 Hom.: 25132

Bravo AF: 0.475

Asia WGS AF: 0.543 AC: 1887 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 05, 2016	Variant summary: The SCN1A c.1028+21T>C variant affects a non-conserved intronic nucleotide. Mutation taster predicts a benign outcome for this variant. This variant was found in 62812/119682 control chromosomes (16581 homozygotes) at a frequency of 0.5248241, which greatly exceeds the maximal expected frequency of a pathogenic SCN1A allele (0.0000179), suggesting this variant is benign. Moreover, the variant was found in an internal sample to co-occur with a pathogenic truncating SCN1A variant, further supporting neutrality. Additionally, several independent peer reviewed publications classified the variant as a polymorphism. Taken together, this variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 73% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 68. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.3
DANN	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs1542484; hg19: chr2-166905375; COSMIC: COSV57684001;