2-166053034-C-T

Variant names:

• chr2-166053034-C-T
• rs3812718
• NM_001165963.4:c.603-91G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

The NM_001165963.4(SCN1A):​c.603-91G>A variant causes a intron change. The variant allele was found at a frequency of 0.534 in 1,421,164 control chromosomes in the GnomAD database, including 205,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18479 hom., cov: 32)
  • Exomes 𝑓: 0.54 (186974 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: drug response reviewed by expert panel B:1 O:2
• Conservation: PhyloP100: 3.74
• Publications: 116 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.14).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.541 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.603-91G>A		intron	N/A	NP_001159435.1
	SCN1A	NM_001202435.3		c.603-91G>A		intron	N/A	NP_001189364.1
	SCN1A	NM_001353948.2		c.603-91G>A		intron	N/A	NP_001340877.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.603-91G>A		intron	N/A	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.603-91G>A		intron	N/A	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.603-91G>A		intron	N/A	ENSP00000364554.3

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73556 AN: 151746 Hom.: 18479 Cov.: 32

Gnomad AFR AF: 0.349

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.539

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.556

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.544

Gnomad OTH AF: 0.480

GnomAD4 exome AF: 0.540 AC: 685527 AN: 1269300 Hom.: 186974 Cov.: 21 AF XY: 0.540 AC XY: 346294 AN XY: 641218

African (AFR) AF: 0.342 AC: 10056 AN: 29368

American (AMR) AF: 0.453 AC: 19890 AN: 43926

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 13486 AN: 24796

East Asian (EAS) AF: 0.554 AC: 21494 AN: 38790

South Asian (SAS) AF: 0.550 AC: 45201 AN: 82174

European-Finnish (FIN) AF: 0.537 AC: 28504 AN: 53088

Middle Eastern (MID) AF: 0.421 AC: 2258 AN: 5358

European-Non Finnish (NFE) AF: 0.550 AC: 516245 AN: 937944

Other (OTH) AF: 0.527 AC: 28393 AN: 53856

GnomAD4 genome AF: 0.484 AC: 73575 AN: 151864 Hom.: 18479 Cov.: 32 AF XY: 0.486 AC XY: 36059 AN XY: 74212

African (AFR) AF: 0.348 AC: 14440 AN: 41464

American (AMR) AF: 0.487 AC: 7401 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 1871 AN: 3470

East Asian (EAS) AF: 0.558 AC: 2877 AN: 5158

South Asian (SAS) AF: 0.556 AC: 2678 AN: 4814

European-Finnish (FIN) AF: 0.538 AC: 5686 AN: 10576

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.544 AC: 36943 AN: 67870

Other (OTH) AF: 0.482 AC: 1019 AN: 2112

Alfa AF: 0.486 Hom.: 16812

Bravo AF: 0.469

Asia WGS AF: 0.544 AC: 1892 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	-	carbamazepine response - Dosage (1)
-	-	-	Febrile seizures, familial, 3a (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.14
CADD	Benign	19
DANN	Benign	0.77
PhyloP100		3.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3812718; hg19: chr2-166909544; COSMIC: COSV57673143;