rs59251406

Variant names:

• chr2-166042275-T-C
• rs59251406
• NM_001165963.4:c.2176+17A>G

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.2176+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,609,914 control chromosomes in the GnomAD database, including 621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene SCN1A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.035 (313 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (308 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.341
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-166042275-T-C is Benign according to our data. Variant chr2-166042275-T-C is described in ClinVar as Benign. ClinVar VariationId is 93637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 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.2176+17A>G		intron	N/A	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.2176+17A>G		intron	N/A	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.2176+17A>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.2176+17A>G		intron	N/A	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.2176+17A>G		intron	N/A	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.2143+17A>G		intron	N/A	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.0352 AC: 5358 AN: 152104 Hom.: 310 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00925 AC: 2296 AN: 248300 AF XY: 0.00648

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.00594

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.00463

GnomAD4 exome AF: 0.00362 AC: 5281 AN: 1457692 Hom.: 308 Cov.: 30 AF XY: 0.00309 AC XY: 2236 AN XY: 724704

African (AFR) AF: 0.125 AC: 4175 AN: 33310

American (AMR) AF: 0.00740 AC: 328 AN: 44324

Ashkenazi Jewish (ASJ) AF: 0.0000770 AC: 2 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.000234 AC: 20 AN: 85372

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53306

Middle Eastern (MID) AF: 0.00766 AC: 44 AN: 5746

European-Non Finnish (NFE) AF: 0.000200 AC: 222 AN: 1109834

Other (OTH) AF: 0.00812 AC: 489 AN: 60224

GnomAD4 genome AF: 0.0353 AC: 5370 AN: 152222 Hom.: 313 Cov.: 32 AF XY: 0.0341 AC XY: 2537 AN XY: 74440

African (AFR) AF: 0.123 AC: 5104 AN: 41522

American (AMR) AF: 0.0130 AC: 199 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 67996

Other (OTH) AF: 0.0170 AC: 36 AN: 2112

Alfa AF: 0.0188 Hom.: 48

Bravo AF: 0.0405

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.38
DANN	Benign	0.51
PhyloP100		-0.34
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: rs59251406; hg19: chr2-166898785;