rs10188577

Variant names:

• chr2-166059387-T-C
• rs10188577
• NM_001165963.4:c.265-699A>G

Variant summary

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

The NM_001165963.4(SCN1A):​c.265-699A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 152,086 control chromosomes in the GnomAD database, including 5,858 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. The gene SCN1A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.26 (5858 hom., cov: 31)
  • Exomes 𝑓: 0.10 (0 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.508
• Publications: 14 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

Specifications for SCN1A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.336 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	NM_001165963.4	MANE Select	c.265-699A>G		intron	N/A	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.265-699A>G		intron	N/A	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.265-699A>G		intron	N/A	NP_001340877.1	P35498-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.265-699A>G		intron	N/A	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.265-699A>G		intron	N/A	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.265-699A>G		intron	N/A	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39622 AN: 151958 Hom.: 5858 Cov.: 31

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.294

GnomAD4 exome AF: 0.100 AC: 1 AN: 10 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 6

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.100 AC: 1 AN: 10

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.261 AC: 39625 AN: 152076 Hom.: 5858 Cov.: 31 AF XY: 0.258 AC XY: 19174 AN XY: 74358

African (AFR) AF: 0.123 AC: 5116 AN: 41518

American (AMR) AF: 0.234 AC: 3577 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1334 AN: 3466

East Asian (EAS) AF: 0.193 AC: 999 AN: 5170

South Asian (SAS) AF: 0.272 AC: 1311 AN: 4818

European-Finnish (FIN) AF: 0.298 AC: 3157 AN: 10580

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.340 AC: 23099 AN: 67940

Other (OTH) AF: 0.298 AC: 628 AN: 2108

Alfa AF: 0.311 Hom.: 19474

Bravo AF: 0.248

Asia WGS AF: 0.244 AC: 847 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.4
DANN	Benign	0.67
PhyloP100		0.51
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: rs10188577; hg19: chr2-166915897;