rs1542484

Variant names:

• chr2-166048865-A-G
• rs1542484
• NM_001165963.4:c.1028+21T>C

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: -0.295
• Publications: 16 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.1028+21T>C		intron_variant	Intron 10 of 28	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.1028+21T>C		intron_variant	Intron 10 of 28		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.1028+21T>C		intron_variant	Intron 9 of 27	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.1028+21T>C		intron_variant	Intron 7 of 25	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.1028+21T>C		intron_variant	Intron 9 of 27	5		ENSP00000386312.1

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

GnomAD2 exomes AF: 0.524 AC: 130644 AN: 249178 AF XY: 0.528

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 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

African (AFR) AF: 0.332 AC: 10363 AN: 31174

American (AMR) AF: 0.505 AC: 22383 AN: 44334

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 13602 AN: 25230

East Asian (EAS) AF: 0.554 AC: 21502 AN: 38846

South Asian (SAS) AF: 0.546 AC: 45586 AN: 83540

European-Finnish (FIN) AF: 0.537 AC: 28583 AN: 53220

Middle Eastern (MID) AF: 0.417 AC: 2311 AN: 5542

European-Non Finnish (NFE) AF: 0.534 AC: 530972 AN: 994848

Other (OTH) AF: 0.519 AC: 28998 AN: 55920

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

African (AFR) AF: 0.349 AC: 14464 AN: 41426

American (AMR) AF: 0.508 AC: 7731 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1869 AN: 3462

East Asian (EAS) AF: 0.557 AC: 2854 AN: 5122

South Asian (SAS) AF: 0.556 AC: 2671 AN: 4808

European-Finnish (FIN) AF: 0.536 AC: 5655 AN: 10544

Middle Eastern (MID) AF: 0.445 AC: 129 AN: 290

European-Non Finnish (NFE) AF: 0.544 AC: 36927 AN: 67846

Other (OTH) AF: 0.486 AC: 1023 AN: 2106

Alfa AF: 0.520 Hom.: 59913

Bravo AF: 0.475

Asia WGS AF: 0.543 AC: 1887 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 05, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

Jul 15, 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 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
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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