chr2-166066849-C-G

Variant names:

• chr2-166066849-C-G
• rs4667869
• NM_001165963.4:c.264+6509G>C

Variant summary

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

The NM_001165963.4(SCN1A):​c.264+6509G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 152,060 control chromosomes in the GnomAD database, including 4,195 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.

• Frequency: Genomes: 𝑓 0.23 (4195 hom., cov: 32)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.406
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	NM_001165963.4	MANE Select	c.264+6509G>C		intron	N/A	NP_001159435.1
	SCN1A	NM_001202435.3		c.264+6509G>C		intron	N/A	NP_001189364.1
	SCN1A	NM_001353948.2		c.264+6509G>C		intron	N/A	NP_001340877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.264+6509G>C		intron	N/A	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.264+6509G>C		intron	N/A	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.264+6509G>C		intron	N/A	ENSP00000364554.3

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34646 AN: 151942 Hom.: 4192 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.207

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.228 AC: 34656 AN: 152060 Hom.: 4195 Cov.: 32 AF XY: 0.233 AC XY: 17343 AN XY: 74310

African (AFR) AF: 0.189 AC: 7852 AN: 41500

American (AMR) AF: 0.280 AC: 4272 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 607 AN: 3464

East Asian (EAS) AF: 0.359 AC: 1852 AN: 5160

South Asian (SAS) AF: 0.282 AC: 1360 AN: 4818

European-Finnish (FIN) AF: 0.282 AC: 2974 AN: 10562

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 15033 AN: 67980

Other (OTH) AF: 0.204 AC: 431 AN: 2114

Alfa AF: 0.142 Hom.: 273

Bravo AF: 0.223

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.9
DANN	Benign	0.49
PhyloP100		-0.41
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: rs4667869; hg19: chr2-166923359;