2-166053185-A-G

Variant names:

• chr2-166053185-A-G
• rs2217199
• NM_001165963.4:c.603-242T>C

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.603-242T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 760,782 control chromosomes in the GnomAD database, including 106,998 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18477 hom., cov: 33)
  • Exomes 𝑓: 0.54 (88521 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.116
• Publications: 5 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=-0.83).
• BP6: Variant 2-166053185-A-G is Benign according to our data. Variant chr2-166053185-A-G is described in ClinVar as Benign. ClinVar VariationId is 669297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165963.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	NM_001165963.4	MANE Select	c.603-242T>C		intron	N/A	NP_001159435.1
	SCN1A	NM_001202435.3		c.603-242T>C		intron	N/A	NP_001189364.1
	SCN1A	NM_001353948.2		c.603-242T>C		intron	N/A	NP_001340877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.603-242T>C		intron	N/A	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.603-242T>C		intron	N/A	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.603-242T>C		intron	N/A	ENSP00000364554.3

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73565 AN: 151806 Hom.: 18477 Cov.: 33

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: 0.537

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.544

Gnomad OTH AF: 0.481

GnomAD4 exome AF: 0.536 AC: 326405 AN: 608858 Hom.: 88521 AF XY: 0.536 AC XY: 175224 AN XY: 326682

African (AFR) AF: 0.347 AC: 5500 AN: 15846

American (AMR) AF: 0.455 AC: 13514 AN: 29710

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 9911 AN: 18158

East Asian (EAS) AF: 0.550 AC: 18937 AN: 34442

South Asian (SAS) AF: 0.551 AC: 32547 AN: 59084

European-Finnish (FIN) AF: 0.535 AC: 25679 AN: 47992

Middle Eastern (MID) AF: 0.435 AC: 1054 AN: 2422

European-Non Finnish (NFE) AF: 0.549 AC: 202889 AN: 369674

Other (OTH) AF: 0.519 AC: 16374 AN: 31530

GnomAD4 genome AF: 0.484 AC: 73585 AN: 151924 Hom.: 18477 Cov.: 33 AF XY: 0.486 AC XY: 36075 AN XY: 74266

African (AFR) AF: 0.348 AC: 14436 AN: 41448

American (AMR) AF: 0.487 AC: 7411 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 1872 AN: 3472

East Asian (EAS) AF: 0.558 AC: 2880 AN: 5164

South Asian (SAS) AF: 0.556 AC: 2674 AN: 4808

European-Finnish (FIN) AF: 0.537 AC: 5674 AN: 10572

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.544 AC: 36957 AN: 67914

Other (OTH) AF: 0.483 AC: 1019 AN: 2110

Alfa AF: 0.503 Hom.: 2550

Bravo AF: 0.469

Asia WGS AF: 0.542 AC: 1887 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.67
DANN	Benign	0.45
PhyloP100		-0.12
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: rs2217199; hg19: chr2-166909695;