2-166058825-C-A

Position:

• chr2-166058825-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001165963.4(SCN1A):​c.265-137G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.692 in 620,674 control chromosomes in the GnomAD database, including 150,744 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34104 hom., cov: 32)
  • Exomes 𝑓: 0.70 (116640 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.576

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-166058825-C-A is Benign according to our data. Variant chr2-166058825-C-A is described in ClinVar as [Benign]. Clinvar id is 669294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.265-137G>T		intron_variant		ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.265-137G>T		intron_variant			NM_001165963.4	ENSP00000501589	P4
SCN1A-AS1	ENST00000651574.1	n.488-16463C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.666 AC: 101064 AN: 151802 Hom.: 34076 Cov.: 32

Gnomad AFR AF: 0.571

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.717

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.757

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.638

GnomAD4 exome AF: 0.701 AC: 328546 AN: 468754 Hom.: 116640 AF XY: 0.698 AC XY: 174992 AN XY: 250670

Gnomad4 AFR exome AF: 0.576

Gnomad4 AMR exome AF: 0.777

Gnomad4 ASJ exome AF: 0.603

Gnomad4 EAS exome AF: 0.895

Gnomad4 SAS exome AF: 0.687

Gnomad4 FIN exome AF: 0.751

Gnomad4 NFE exome AF: 0.683

Gnomad4 OTH exome AF: 0.675

GnomAD4 genome AF: 0.666 AC: 101136 AN: 151920 Hom.: 34104 Cov.: 32 AF XY: 0.672 AC XY: 49880 AN XY: 74246

Gnomad4 AFR AF: 0.570

Gnomad4 AMR AF: 0.718

Gnomad4 ASJ AF: 0.603

Gnomad4 EAS AF: 0.891

Gnomad4 SAS AF: 0.709

Gnomad4 FIN AF: 0.757

Gnomad4 NFE AF: 0.683

Gnomad4 OTH AF: 0.641

Alfa AF: 0.670 Hom.: 8816

Bravo AF: 0.658

Asia WGS AF: 0.772 AC: 2684 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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	-0.90
CADD	Benign	1.2
DANN	Benign	0.50

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: rs10930201; hg19: chr2-166915335;