chr2-166053049-C-A

Variant names:

• chr2-166053049-C-A
• rs3812719
• NM_001165963.4:c.603-106G>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001165963.4(SCN1A):​c.603-106G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 1,421,714 control chromosomes in the GnomAD database, including 353,248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34169 hom., cov: 33)
  • Exomes 𝑓: 0.71 (319079 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.31
• Publications: 8 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 2-166053049-C-A is Benign according to our data. Variant chr2-166053049-C-A is described in ClinVar as Benign. ClinVar VariationId is 674938.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.603-106G>T		intron_variant	Intron 7 of 28	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.603-106G>T		intron_variant	Intron 7 of 28		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.603-106G>T		intron_variant	Intron 6 of 27	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.603-106G>T		intron_variant	Intron 4 of 25	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.603-106G>T		intron_variant	Intron 6 of 27	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101163 AN: 151782 Hom.: 34141 Cov.: 33

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.717

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.756

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.637

GnomAD4 exome AF: 0.707 AC: 897554 AN: 1269814 Hom.: 319079 Cov.: 23 AF XY: 0.703 AC XY: 450921 AN XY: 641396

African (AFR) AF: 0.584 AC: 17127 AN: 29326

American (AMR) AF: 0.790 AC: 34822 AN: 44094

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 14981 AN: 24774

East Asian (EAS) AF: 0.896 AC: 34791 AN: 38826

South Asian (SAS) AF: 0.686 AC: 56333 AN: 82106

European-Finnish (FIN) AF: 0.749 AC: 39769 AN: 53128

Middle Eastern (MID) AF: 0.502 AC: 2694 AN: 5370

European-Non Finnish (NFE) AF: 0.703 AC: 660059 AN: 938352

Other (OTH) AF: 0.687 AC: 36978 AN: 53838

GnomAD4 genome AF: 0.666 AC: 101235 AN: 151900 Hom.: 34169 Cov.: 33 AF XY: 0.672 AC XY: 49924 AN XY: 74256

African (AFR) AF: 0.574 AC: 23764 AN: 41426

American (AMR) AF: 0.718 AC: 10926 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2088 AN: 3466

East Asian (EAS) AF: 0.891 AC: 4599 AN: 5162

South Asian (SAS) AF: 0.708 AC: 3417 AN: 4826

European-Finnish (FIN) AF: 0.756 AC: 8009 AN: 10594

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.683 AC: 46347 AN: 67896

Other (OTH) AF: 0.640 AC: 1350 AN: 2110

Alfa AF: 0.666 Hom.: 12316

Bravo AF: 0.659

Asia WGS AF: 0.773 AC: 2688 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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. -

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 81% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 75. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.79
PhyloP100		1.3
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: rs3812719; hg19: chr2-166909559;