rs490317

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165963.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	NM_001165963.4	MANE Select	c.2416-72G>A		intron	N/A	NP_001159435.1
	SCN1A	NM_001202435.3		c.2416-72G>A		intron	N/A	NP_001189364.1
	SCN1A	NM_001353948.2		c.2416-72G>A		intron	N/A	NP_001340877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.2416-72G>A		intron	N/A	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.2416-72G>A		intron	N/A	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.2383-72G>A		intron	N/A	ENSP00000364554.3

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

African (AFR) AF: 0.0882 AC: 2432 AN: 27562

American (AMR) AF: 0.178 AC: 7333 AN: 41132

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 7807 AN: 24106

East Asian (EAS) AF: 0.0853 AC: 3172 AN: 37170

South Asian (SAS) AF: 0.226 AC: 17460 AN: 77238

European-Finnish (FIN) AF: 0.203 AC: 10587 AN: 52100

Middle Eastern (MID) AF: 0.383 AC: 1838 AN: 4802

European-Non Finnish (NFE) AF: 0.280 AC: 244483 AN: 874332

Other (OTH) AF: 0.261 AC: 13356 AN: 51144

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

African (AFR) AF: 0.0931 AC: 3866 AN: 41526

American (AMR) AF: 0.227 AC: 3462 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1105 AN: 3472

East Asian (EAS) AF: 0.0934 AC: 483 AN: 5170

South Asian (SAS) AF: 0.203 AC: 980 AN: 4816

European-Finnish (FIN) AF: 0.190 AC: 2003 AN: 10548

Middle Eastern (MID) AF: 0.390 AC: 114 AN: 292

European-Non Finnish (NFE) AF: 0.282 AC: 19165 AN: 67948

Other (OTH) AF: 0.264 AC: 559 AN: 2114

Alfa AF: 0.237 Hom.: 636

Bravo AF: 0.210

Asia WGS AF: 0.151 AC: 527 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.4
DANN	Benign	0.68
PhyloP100		-1.9
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: rs490317; hg19: chr2-166896178; COSMIC: COSV57668281; COSMIC: COSV57668281;