rs140237315

Variant names:

• chr2-165991857-C-T
• rs140237315
• NM_001165963.4:c.5418G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001165963.4(SCN1A):​c.5418G>A​(p.Glu1806Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,613,934 control chromosomes in the GnomAD database, including 240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene SCN1A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0096 (17 hom., cov: 32)
  • Exomes 𝑓: 0.012 (223 hom.)
• Consequence: SCN1A NM_001165963.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.99
• Publications: 7 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)

LOC102724058 (HGNC:):

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-165991857-C-T is Benign according to our data. Variant chr2-165991857-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00955 (1453/152142) while in subpopulation SAS AF = 0.0326 (157/4820). AF 95% confidence interval is 0.0284. There are 17 homozygotes in GnomAd4. There are 672 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1453 AD,Unknown gene.

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.5418G>A	p.Glu1806Glu	synonymous	Exon 29 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.5418G>A	p.Glu1806Glu	synonymous	Exon 28 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.5418G>A	p.Glu1806Glu	synonymous	Exon 27 of 27	NP_001340877.1	P35498-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.5418G>A	p.Glu1806Glu	synonymous	Exon 29 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.5418G>A	p.Glu1806Glu	synonymous	Exon 28 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.5385G>A	p.Glu1795Glu	synonymous	Exon 26 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.00956 AC: 1454 AN: 152024 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0328

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0136 AC: 3412 AN: 251232 AF XY: 0.0155

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00749

Gnomad ASJ exome AF: 0.0288

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0125 AC: 18206 AN: 1461792 Hom.: 223 Cov.: 31 AF XY: 0.0135 AC XY: 9848 AN XY: 727204

African (AFR) AF: 0.00230 AC: 77 AN: 33468

American (AMR) AF: 0.00821 AC: 367 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0298 AC: 778 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0403 AC: 3478 AN: 86256

European-Finnish (FIN) AF: 0.00172 AC: 92 AN: 53418

Middle Eastern (MID) AF: 0.0428 AC: 247 AN: 5768

European-Non Finnish (NFE) AF: 0.0110 AC: 12211 AN: 1111946

Other (OTH) AF: 0.0158 AC: 953 AN: 60396

GnomAD4 genome AF: 0.00955 AC: 1453 AN: 152142 Hom.: 17 Cov.: 32 AF XY: 0.00903 AC XY: 672 AN XY: 74378

African (AFR) AF: 0.00301 AC: 125 AN: 41534

American (AMR) AF: 0.0102 AC: 155 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 96 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.0326 AC: 157 AN: 4820

European-Finnish (FIN) AF: 0.000943 AC: 10 AN: 10606

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 821 AN: 67986

Other (OTH) AF: 0.0156 AC: 33 AN: 2114

Alfa AF: 0.0129 Hom.: 6

Bravo AF: 0.00931

EpiCase AF: 0.0169

EpiControl AF: 0.0157

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Epilepsy (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 2 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Migraine, familial hemiplegic, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	10
DANN	Benign	0.48
PhyloP100		2.0
Mutation Taster		=98/2	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: rs140237315; hg19: chr2-166848367; COSMIC: COSV57676706; COSMIC: COSV57676706;