rs490317

Variant names:

• chr2-166039668-C-T
• rs490317
• NM_001165963.4:c.2416-72G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001165963.4(SCN1A):​c.2416-72G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,341,646 control chromosomes in the GnomAD database, including 45,436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (3867 hom., cov: 32)
  • Exomes 𝑓: 0.26 (41569 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.92

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-166039668-C-T is Benign according to our data. Variant chr2-166039668-C-T is described in ClinVar as [Benign]. Clinvar id is 3256826.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.2416-72G>A		intron_variant	Intron 16 of 28	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.2416-72G>A		intron_variant	Intron 16 of 28		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.2416-72G>A		intron_variant	Intron 15 of 27	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.2383-72G>A		intron_variant	Intron 13 of 25	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.2332-72G>A		intron_variant	Intron 13 of 25	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32034 AN: 151944 Hom.: 3870 Cov.: 32

Gnomad AFR AF: 0.0933

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.0934

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.267

GnomAD4 exome AF: 0.259 AC: 308468 AN: 1189586 Hom.: 41569 AF XY: 0.261 AC XY: 157022 AN XY: 602536

Gnomad4 AFR exome AF: 0.0882

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.324

Gnomad4 EAS exome AF: 0.0853

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.203

Gnomad4 NFE exome AF: 0.280

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.211 AC: 32028 AN: 152060 Hom.: 3867 Cov.: 32 AF XY: 0.206 AC XY: 15299 AN XY: 74334

Gnomad4 AFR AF: 0.0931

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.0934

Gnomad4 SAS AF: 0.203

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.282

Gnomad4 OTH AF: 0.264

Alfa AF: 0.244 Hom.: 632

Bravo AF: 0.210

Asia WGS AF: 0.151 AC: 527 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 26% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 24. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.4
DANN	Benign	0.68

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: rs490317; hg19: chr2-166896178; COSMIC: COSV57668281; COSMIC: COSV57668281;