rs8191987

Variant names:

• chr2-166058504-A-G
• rs8191987
• NM_001165963.4:c.383+66T>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.383+66T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 883,288 control chromosomes in the GnomAD database, including 15,466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3124 hom., cov: 32)
  • Exomes 𝑓: 0.17 (12342 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.57
• Publications: 7 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=-0.63).
• BP6: Variant 2-166058504-A-G is Benign according to our data. Variant chr2-166058504-A-G is described in ClinVar as Benign. ClinVar VariationId is 670595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.383+66T>C		intron_variant	Intron 5 of 28	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.383+66T>C		intron_variant	Intron 5 of 28		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.383+66T>C		intron_variant	Intron 4 of 27	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.383+66T>C		intron_variant	Intron 2 of 25	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.383+66T>C		intron_variant	Intron 4 of 27	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28740 AN: 151870 Hom.: 3116 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.169 AC: 123819 AN: 731300 Hom.: 12342 AF XY: 0.164 AC XY: 63318 AN XY: 386838

African (AFR) AF: 0.260 AC: 4844 AN: 18632

American (AMR) AF: 0.338 AC: 12848 AN: 38052

Ashkenazi Jewish (ASJ) AF: 0.0583 AC: 1160 AN: 19894

East Asian (EAS) AF: 0.343 AC: 12196 AN: 35600

South Asian (SAS) AF: 0.134 AC: 8856 AN: 65894

European-Finnish (FIN) AF: 0.211 AC: 10769 AN: 50998

Middle Eastern (MID) AF: 0.0768 AC: 303 AN: 3946

European-Non Finnish (NFE) AF: 0.145 AC: 67126 AN: 462682

Other (OTH) AF: 0.161 AC: 5717 AN: 35602

GnomAD4 genome AF: 0.189 AC: 28791 AN: 151988 Hom.: 3124 Cov.: 32 AF XY: 0.193 AC XY: 14369 AN XY: 74266

African (AFR) AF: 0.254 AC: 10526 AN: 41480

American (AMR) AF: 0.232 AC: 3529 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 219 AN: 3470

East Asian (EAS) AF: 0.331 AC: 1709 AN: 5164

South Asian (SAS) AF: 0.152 AC: 733 AN: 4828

European-Finnish (FIN) AF: 0.218 AC: 2307 AN: 10582

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9355 AN: 67920

Other (OTH) AF: 0.160 AC: 338 AN: 2110

Alfa AF: 0.166 Hom.: 306

Bravo AF: 0.199

Asia WGS AF: 0.231 AC: 800 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 18, 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. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 40% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 37. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Benign	0.86
PhyloP100		1.6
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: rs8191987; hg19: chr2-166915014; COSMIC: COSV57686390;