chr2-166053034-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4 BP6_Strong 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

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.14).
• BP6: Variant 2-166053034-C-T is Benign according to our data. Variant chr2-166053034-C-T is described in ClinVar as [drug_response]. Clinvar id is 12897.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {drug_response=1, Benign=1}.
• 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	ENST00000409050.1	c.603-91G>A		intron_variant	Intron 4 of 25	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

Gnomad4 AFR exome AF: 0.342

Gnomad4 AMR exome AF: 0.453

Gnomad4 ASJ exome AF: 0.544

Gnomad4 EAS exome AF: 0.554

Gnomad4 SAS exome AF: 0.550

Gnomad4 FIN exome AF: 0.537

Gnomad4 NFE exome AF: 0.550

Gnomad4 OTH exome AF: 0.527

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

Gnomad4 AFR AF: 0.348

Gnomad4 AMR AF: 0.487

Gnomad4 ASJ AF: 0.539

Gnomad4 EAS AF: 0.558

Gnomad4 SAS AF: 0.556

Gnomad4 FIN AF: 0.538

Gnomad4 NFE AF: 0.544

Gnomad4 OTH AF: 0.482

Alfa AF: 0.505 Hom.: 8243

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

Early infantile epileptic encephalopathy with suppression bursts 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

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

Publications

LitVar

Other links and lift over

dbSNP: rs3812718; hg19: chr2-166909544; COSMIC: COSV57673143;