2-166039215-T-C

Variant names:

• chr2-166039215-T-C
• rs1019724
• NM_001165963.4:c.2589+208A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001165963.4(SCN1A):​c.2589+208A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.738 in 152,120 control chromosomes in the GnomAD database, including 41,785 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.74 (41785 hom., cov: 33)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.63

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-166039215-T-C is Benign according to our data. Variant chr2-166039215-T-C is described in ClinVar as [Benign]. Clinvar id is 669303.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.2589+208A>G		intron_variant	Intron 17 of 28	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.2589+208A>G		intron_variant	Intron 17 of 28		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.2589+208A>G		intron_variant	Intron 16 of 27	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.2556+208A>G		intron_variant	Intron 14 of 25	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.2505+208A>G		intron_variant	Intron 14 of 25	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes AF: 0.738 AC: 112103 AN: 152002 Hom.: 41740 Cov.: 33

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.890

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.756

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.680

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

GnomAD4 genome AF: 0.738 AC: 112209 AN: 152120 Hom.: 41785 Cov.: 33 AF XY: 0.741 AC XY: 55098 AN XY: 74354

Gnomad4 AFR AF: 0.823

Gnomad4 AMR AF: 0.742

Gnomad4 ASJ AF: 0.603

Gnomad4 EAS AF: 0.890

Gnomad4 SAS AF: 0.709

Gnomad4 FIN AF: 0.756

Gnomad4 NFE AF: 0.683

Gnomad4 OTH AF: 0.683

Alfa AF: 0.614 Hom.: 1733

Bravo AF: 0.741

Asia WGS AF: 0.789 AC: 2743 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.31
DANN	Benign	0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs1019724; hg19: chr2-166895725;