rs1019723

Variant names:

• chr2-166039251-A-G
• rs1019723
• NM_001165963.4:c.2589+172T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001165963.4(SCN1A):​c.2589+172T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 152,070 control chromosomes in the GnomAD database, including 19,854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.48 (19854 hom., cov: 33)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.10
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-166039251-A-G is Benign according to our data. Variant chr2-166039251-A-G is described in ClinVar as Benign. ClinVar VariationId is 669302.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.2589+172T>C		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+172T>C		intron_variant	Intron 17 of 28		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.2589+172T>C		intron_variant	Intron 16 of 27	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.2556+172T>C		intron_variant	Intron 14 of 25	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.2505+172T>C		intron_variant	Intron 16 of 27	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes AF: 0.481 AC: 73071 AN: 151952 Hom.: 19809 Cov.: 33

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.697

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.391

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

GnomAD4 genome AF: 0.481 AC: 73176 AN: 152070 Hom.: 19854 Cov.: 33 AF XY: 0.486 AC XY: 36164 AN XY: 74356

African (AFR) AF: 0.718 AC: 29768 AN: 41464

American (AMR) AF: 0.510 AC: 7788 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 753 AN: 3470

East Asian (EAS) AF: 0.697 AC: 3608 AN: 5176

South Asian (SAS) AF: 0.416 AC: 2002 AN: 4818

European-Finnish (FIN) AF: 0.456 AC: 4814 AN: 10568

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.342 AC: 23281 AN: 67978

Other (OTH) AF: 0.390 AC: 824 AN: 2114

Alfa AF: 0.440 Hom.: 2151

Bravo AF: 0.498

Asia WGS AF: 0.539 AC: 1873 AN: 3474

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	-0.87
CADD	Benign	3.7
DANN	Benign	0.35
PhyloP100		-1.1
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: rs1019723; hg19: chr2-166895761;