rs7580482

Variant names:

• chr2-166046935-T-C
• rs7580482
• NM_001165963.4:c.1212A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-166046935-T-C
• chr2-166046935-T-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001165963.4(SCN1A):​c.1212A>G​(p.Val404Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 1,613,478 control chromosomes in the GnomAD database, including 389,946 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 0.67 (34209 hom., cov: 32)
  • Exomes 𝑓: 0.70 (355737 hom.)
• Consequence: SCN1A NM_001165963.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.280
• Publications: 32 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-166046935-T-C is Benign according to our data. Variant chr2-166046935-T-C is described in ClinVar as Benign. ClinVar VariationId is 36751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.87 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.1212A>G	p.Val404Val	synonymous	Exon 12 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.1212A>G	p.Val404Val	synonymous	Exon 11 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.1212A>G	p.Val404Val	synonymous	Exon 10 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.1212A>G	p.Val404Val	synonymous	Exon 12 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.1212A>G	p.Val404Val	synonymous	Exon 11 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.1212A>G	p.Val404Val	synonymous	Exon 9 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101261 AN: 151924 Hom.: 34181 Cov.: 32

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.717

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.757

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.639

GnomAD2 exomes AF: 0.708 AC: 177809 AN: 251212 AF XY: 0.703

Gnomad AFR exome AF: 0.575

Gnomad AMR exome AF: 0.798

Gnomad ASJ exome AF: 0.599

Gnomad EAS exome AF: 0.897

Gnomad FIN exome AF: 0.745

Gnomad NFE exome AF: 0.679

Gnomad OTH exome AF: 0.669

GnomAD4 exome AF: 0.695 AC: 1016360 AN: 1461436 Hom.: 355737 Cov.: 61 AF XY: 0.693 AC XY: 503895 AN XY: 727034

African (AFR) AF: 0.570 AC: 19078 AN: 33462

American (AMR) AF: 0.790 AC: 35313 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 15710 AN: 26128

East Asian (EAS) AF: 0.895 AC: 35536 AN: 39688

South Asian (SAS) AF: 0.683 AC: 58880 AN: 86250

European-Finnish (FIN) AF: 0.748 AC: 39967 AN: 53416

Middle Eastern (MID) AF: 0.501 AC: 2886 AN: 5764

European-Non Finnish (NFE) AF: 0.691 AC: 767910 AN: 1111632

Other (OTH) AF: 0.680 AC: 41080 AN: 60382

GnomAD4 genome AF: 0.666 AC: 101332 AN: 152042 Hom.: 34209 Cov.: 32 AF XY: 0.672 AC XY: 49971 AN XY: 74326

African (AFR) AF: 0.574 AC: 23787 AN: 41454

American (AMR) AF: 0.718 AC: 10948 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2091 AN: 3472

East Asian (EAS) AF: 0.891 AC: 4618 AN: 5182

South Asian (SAS) AF: 0.708 AC: 3417 AN: 4824

European-Finnish (FIN) AF: 0.757 AC: 8002 AN: 10570

Middle Eastern (MID) AF: 0.503 AC: 147 AN: 292

European-Non Finnish (NFE) AF: 0.682 AC: 46383 AN: 67980

Other (OTH) AF: 0.641 AC: 1351 AN: 2106

Alfa AF: 0.668 Hom.: 22171

Bravo AF: 0.659

Asia WGS AF: 0.772 AC: 2686 AN: 3478

EpiCase AF: 0.674

EpiControl AF: 0.656

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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)
-	-	1	Severe myoclonic epilepsy in infancy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.5
DANN	Benign	0.74
PhyloP100		0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs7580482; hg19: chr2-166903445; COSMIC: COSV57690599;