2-166058825-C-A

Variant names:

• chr2-166058825-C-A
• rs10930201
• NM_001165963.4:c.265-137G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 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 -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 VariationId 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 rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.265-137G>T		intron_variant	Intron 4 of 28	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.265-137G>T		intron_variant	Intron 4 of 28		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.265-137G>T		intron_variant	Intron 3 of 27	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.265-137G>T		intron_variant	Intron 1 of 25	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.265-137G>T		intron_variant	Intron 3 of 27	5		ENSP00000386312.1

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

African (AFR) AF: 0.576 AC: 7193 AN: 12480

American (AMR) AF: 0.777 AC: 19027 AN: 24476

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 8936 AN: 14818

East Asian (EAS) AF: 0.895 AC: 26917 AN: 30080

South Asian (SAS) AF: 0.687 AC: 33064 AN: 48132

European-Finnish (FIN) AF: 0.751 AC: 30296 AN: 40348

Middle Eastern (MID) AF: 0.508 AC: 1169 AN: 2302

European-Non Finnish (NFE) AF: 0.683 AC: 184604 AN: 270444

Other (OTH) AF: 0.675 AC: 17340 AN: 25674

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

African (AFR) AF: 0.570 AC: 23629 AN: 41426

American (AMR) AF: 0.718 AC: 10958 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2089 AN: 3464

East Asian (EAS) AF: 0.891 AC: 4601 AN: 5164

South Asian (SAS) AF: 0.709 AC: 3418 AN: 4822

European-Finnish (FIN) AF: 0.757 AC: 8011 AN: 10584

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.683 AC: 46348 AN: 67890

Other (OTH) AF: 0.641 AC: 1350 AN: 2106

Alfa AF: 0.669 Hom.: 8945

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.90
CADD	Benign	1.2
DANN	Benign	0.50
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10930201; hg19: chr2-166915335;