rs150570058

chr2-165991989-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001165963.4(SCN1A):c.5286A>G(p.Gly1762=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,830 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (3 hom.)
• Consequence: SCN1A NM_001165963.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.54

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)

LOC102724058 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-165991989-T-C is Benign according to our data. Variant chr2-165991989-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 195943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.54 with no splicing effect.
• BS2: High AC in GnomAd at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.5286A>G	p.Gly1762=	synonymous_variant	29/29	ENST00000674923.1
LOC102724058	NR_110598.1	n.176-23624T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.5286A>G	p.Gly1762=	synonymous_variant	29/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.193-23624T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 151906 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00368

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000756 AC: 190 AN: 251252 Hom.: 2 AF XY: 0.000523 AC XY: 71 AN XY: 135790

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00512

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000175 AC: 256 AN: 1461806 Hom.: 3 Cov.: 31 AF XY: 0.000132 AC XY: 96 AN XY: 727212

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00474

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000421 AC: 64 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74318

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00368

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000201 Hom.: 0

Bravo AF: 0.000903

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 29, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	SCN1A: BP4, BP7, BS1, BS2 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	8.4
Dann	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs150570058; hg19: chr2-166848499;