2-166055402-G-A

Variant names:

• chr2-166055402-G-A
• rs922224
• NM_001165963.4:c.474-636C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001165963.4(SCN1A):​c.474-636C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 151,634 control chromosomes in the GnomAD database, including 18,464 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 0.48 (18464 hom., cov: 31)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.331
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.474-636C>T		intron_variant	Intron 6 of 28	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.474-636C>T		intron_variant	Intron 6 of 28		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.474-636C>T		intron_variant	Intron 5 of 27	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.474-636C>T		intron_variant	Intron 3 of 25	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.474-636C>T		intron_variant	Intron 5 of 27	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73489 AN: 151516 Hom.: 18464 Cov.: 31

Gnomad AFR AF: 0.349

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.539

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.480

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.485 AC: 73509 AN: 151634 Hom.: 18464 Cov.: 31 AF XY: 0.486 AC XY: 36033 AN XY: 74094

African (AFR) AF: 0.349 AC: 14436 AN: 41394

American (AMR) AF: 0.487 AC: 7385 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 1868 AN: 3464

East Asian (EAS) AF: 0.558 AC: 2876 AN: 5154

South Asian (SAS) AF: 0.557 AC: 2684 AN: 4818

European-Finnish (FIN) AF: 0.538 AC: 5654 AN: 10502

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.544 AC: 36930 AN: 67830

Other (OTH) AF: 0.482 AC: 1016 AN: 2106

Alfa AF: 0.508 Hom.: 9479

Bravo AF: 0.469

Asia WGS AF: 0.540 AC: 1875 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.0
DANN	Benign	0.36
PhyloP100		-0.33
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: rs922224; hg19: chr2-166911912;