rs7601520

Positions:

• chr2-166036571-G-A
• chr2-166036571-G-C

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.2947-41C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.705 in 1,591,596 control chromosomes in the GnomAD database, including 398,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41729 hom., cov: 31)
  • Exomes 𝑓: 0.70 (357155 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.240

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=-0.88).
• BP6: Variant 2-166036571-G-A is Benign according to our data. Variant chr2-166036571-G-A is described in ClinVar as [Benign]. Clinvar id is 487362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.2947-41C>T		intron_variant		ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.2947-41C>T		intron_variant			NM_001165963.4	ENSP00000501589	P4
SCN1A-AS1	ENST00000651574.1	n.487+441G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.737 AC: 112008 AN: 151904 Hom.: 41684 Cov.: 31

Gnomad AFR AF: 0.823

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.757

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.681

GnomAD3 exomes AF: 0.724 AC: 170886 AN: 235970 Hom.: 62678 AF XY: 0.714 AC XY: 91632 AN XY: 128372

Gnomad AFR exome AF: 0.828

Gnomad AMR exome AF: 0.808

Gnomad ASJ exome AF: 0.598

Gnomad EAS exome AF: 0.895

Gnomad SAS exome AF: 0.685

Gnomad FIN exome AF: 0.745

Gnomad NFE exome AF: 0.676

Gnomad OTH exome AF: 0.675

GnomAD4 exome AF: 0.702 AC: 1010489 AN: 1439574 Hom.: 357155 Cov.: 27 AF XY: 0.698 AC XY: 500452 AN XY: 716468

Gnomad4 AFR exome AF: 0.826

Gnomad4 AMR exome AF: 0.802

Gnomad4 ASJ exome AF: 0.601

Gnomad4 EAS exome AF: 0.895

Gnomad4 SAS exome AF: 0.682

Gnomad4 FIN exome AF: 0.748

Gnomad4 NFE exome AF: 0.690

Gnomad4 OTH exome AF: 0.695

GnomAD4 genome AF: 0.737 AC: 112114 AN: 152022 Hom.: 41729 Cov.: 31 AF XY: 0.741 AC XY: 55045 AN XY: 74296

Gnomad4 AFR AF: 0.823

Gnomad4 AMR AF: 0.742

Gnomad4 ASJ AF: 0.603

Gnomad4 EAS AF: 0.891

Gnomad4 SAS AF: 0.709

Gnomad4 FIN AF: 0.757

Gnomad4 NFE AF: 0.682

Gnomad4 OTH AF: 0.683

Alfa AF: 0.688 Hom.: 7171

Bravo AF: 0.740

Asia WGS AF: 0.790 AC: 2748 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 89% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 83. Only high quality variants are reported. -

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
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: rs7601520; hg19: chr2-166893081;