rs140237315

chr2-165991857-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001165963.4(SCN1A):c.5418G>A(p.Glu1806=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,613,934 control chromosomes in the GnomAD database, including 240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (17 hom., cov: 32)
  • Exomes 𝑓: 0.012 (223 hom.)
• Consequence: SCN1A NM_001165963.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.99

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-165991857-C-T is Benign according to our data. Variant chr2-165991857-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165991857-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00955 (1453/152142) while in subpopulation SAS AF= 0.0326 (157/4820). AF 95% confidence interval is 0.0284. There are 17 homozygotes in gnomad4. There are 672 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1454 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.5418G>A	p.Glu1806=	synonymous_variant	29/29	ENST00000674923.1
LOC102724058	NR_110598.1	n.176-23756C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.5418G>A	p.Glu1806=	synonymous_variant	29/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.193-23756C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00956 AC: 1454 AN: 152024 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0328

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0136 AC: 3412 AN: 251232 Hom.: 51 AF XY: 0.0155 AC XY: 2102 AN XY: 135784

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00749

Gnomad ASJ exome AF: 0.0288

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0406

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0125 AC: 18206 AN: 1461792 Hom.: 223 Cov.: 31 AF XY: 0.0135 AC XY: 9848 AN XY: 727204

Gnomad4 AFR exome AF: 0.00230

Gnomad4 AMR exome AF: 0.00821

Gnomad4 ASJ exome AF: 0.0298

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0403

Gnomad4 FIN exome AF: 0.00172

Gnomad4 NFE exome AF: 0.0110

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.00955 AC: 1453 AN: 152142 Hom.: 17 Cov.: 32 AF XY: 0.00903 AC XY: 672 AN XY: 74378

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0326

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0129 Hom.: 6

Bravo AF: 0.00931

EpiCase AF: 0.0169

EpiControl AF: 0.0157

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 10, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Migraine, familial hemiplegic, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2016

This alteration is classified as 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

Feb 01, 2024

- -

Generalized epilepsy with febrile seizures plus, type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	10
Dann	Benign	0.48

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: rs140237315; hg19: chr2-166848367; COSMIC: COSV57676706; COSMIC: COSV57676706;