chr2-166041354-A-G

Variant names:

• chr2-166041354-A-G
• rs6432860
• NM_001165963.4:c.2292T>C

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.2292T>C​(p.Val764Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 1,613,016 control chromosomes in the GnomAD database, including 404,607 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V764V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.74 (41728 hom., cov: 30)
  • Exomes 𝑓: 0.70 (362879 hom.)
• Consequence: SCN1A NM_001165963.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.608
• Publications: 54 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-166041354-A-G is Benign according to our data. Variant chr2-166041354-A-G is described in ClinVar as Benign. ClinVar VariationId is 36752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.608 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.2292T>C	p.Val764Val	synonymous	Exon 16 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.2292T>C	p.Val764Val	synonymous	Exon 15 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.2292T>C	p.Val764Val	synonymous	Exon 14 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.2292T>C	p.Val764Val	synonymous	Exon 16 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.2292T>C	p.Val764Val	synonymous	Exon 15 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.2259T>C	p.Val753Val	synonymous	Exon 13 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.737 AC: 111953 AN: 151804 Hom.: 41683 Cov.: 30

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.679

GnomAD2 exomes AF: 0.726 AC: 182465 AN: 251300 AF XY: 0.715

Gnomad AFR exome AF: 0.830

Gnomad AMR exome AF: 0.809

Gnomad ASJ exome AF: 0.599

Gnomad EAS exome AF: 0.896

Gnomad FIN exome AF: 0.745

Gnomad NFE exome AF: 0.679

Gnomad OTH exome AF: 0.677

GnomAD4 exome AF: 0.703 AC: 1026435 AN: 1461094 Hom.: 362879 Cov.: 42 AF XY: 0.699 AC XY: 508089 AN XY: 726928

African (AFR) AF: 0.827 AC: 27688 AN: 33472

American (AMR) AF: 0.803 AC: 35893 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 15710 AN: 26126

East Asian (EAS) AF: 0.895 AC: 35526 AN: 39680

South Asian (SAS) AF: 0.683 AC: 58908 AN: 86238

European-Finnish (FIN) AF: 0.748 AC: 39968 AN: 53414

Middle Eastern (MID) AF: 0.512 AC: 2942 AN: 5748

European-Non Finnish (NFE) AF: 0.691 AC: 767795 AN: 1111334

Other (OTH) AF: 0.696 AC: 42005 AN: 60360

GnomAD4 genome AF: 0.738 AC: 112059 AN: 151922 Hom.: 41728 Cov.: 30 AF XY: 0.741 AC XY: 55013 AN XY: 74254

African (AFR) AF: 0.823 AC: 34126 AN: 41442

American (AMR) AF: 0.743 AC: 11338 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2090 AN: 3470

East Asian (EAS) AF: 0.891 AC: 4606 AN: 5168

South Asian (SAS) AF: 0.709 AC: 3414 AN: 4812

European-Finnish (FIN) AF: 0.755 AC: 7968 AN: 10550

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.682 AC: 46340 AN: 67898

Other (OTH) AF: 0.682 AC: 1436 AN: 2106

Alfa AF: 0.703 Hom.: 76350

Bravo AF: 0.741

Asia WGS AF: 0.790 AC: 2745 AN: 3476

EpiCase AF: 0.674

EpiControl AF: 0.656

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Epilepsy (1)
-	-	1	Generalized epilepsy with febrile seizures plus (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	-0.74
CADD	Benign	0.43
DANN	Benign	0.61
PhyloP100		-0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6432860; hg19: chr2-166897864; COSMIC: COSV57690570; COSMIC: COSV57690570;