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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.603-91G>A		intron_variant	Intron 7 of 28	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.603-91G>A		intron_variant	Intron 7 of 28		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.603-91G>A		intron_variant	Intron 6 of 27	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.603-91G>A		intron_variant	Intron 4 of 25	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.603-91G>A		intron_variant	Intron 6 of 27	5		ENSP00000386312.1

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

Significance: drug response

Submissions summary: Benign:1 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Developmental and epileptic encephalopathy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

carbamazepine response - Dosage Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Dosage

Febrile seizures, familial, 3a Other:1

Dec 01, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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;