rs7580482

Positions:

• chr2-166046935-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001165963.4(SCN1A):​c.1212A>G​(p.Val404Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 1,613,478 control chromosomes in the GnomAD database, including 389,946 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34209 hom., cov: 32)
  • Exomes 𝑓: 0.70 (355737 hom.)
• Consequence: SCN1A NM_001165963.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.280

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-166046935-T-C is Benign according to our data. Variant chr2-166046935-T-C is described in ClinVar as [Benign]. Clinvar id is 36751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166046935-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.87 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.1212A>G	p.Val404Val	synonymous_variant	12/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.1212A>G	p.Val404Val	synonymous_variant	12/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.1212A>G	p.Val404Val	synonymous_variant	11/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.1212A>G	p.Val404Val	synonymous_variant	9/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.1212A>G	p.Val404Val	synonymous_variant	9/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101261 AN: 151924 Hom.: 34181 Cov.: 32

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.717

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.757

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.639

GnomAD3 exomes AF: 0.708 AC: 177809 AN: 251212 Hom.: 63943 AF XY: 0.703 AC XY: 95409 AN XY: 135782

Gnomad AFR exome AF: 0.575

Gnomad AMR exome AF: 0.798

Gnomad ASJ exome AF: 0.599

Gnomad EAS exome AF: 0.897

Gnomad SAS exome AF: 0.686

Gnomad FIN exome AF: 0.745

Gnomad NFE exome AF: 0.679

Gnomad OTH exome AF: 0.669

GnomAD4 exome AF: 0.695 AC: 1016360 AN: 1461436 Hom.: 355737 Cov.: 61 AF XY: 0.693 AC XY: 503895 AN XY: 727034

Gnomad4 AFR exome AF: 0.570

Gnomad4 AMR exome AF: 0.790

Gnomad4 ASJ exome AF: 0.601

Gnomad4 EAS exome AF: 0.895

Gnomad4 SAS exome AF: 0.683

Gnomad4 FIN exome AF: 0.748

Gnomad4 NFE exome AF: 0.691

Gnomad4 OTH exome AF: 0.680

GnomAD4 genome AF: 0.666 AC: 101332 AN: 152042 Hom.: 34209 Cov.: 32 AF XY: 0.672 AC XY: 49971 AN XY: 74326

Gnomad4 AFR AF: 0.574

Gnomad4 AMR AF: 0.718

Gnomad4 ASJ AF: 0.602

Gnomad4 EAS AF: 0.891

Gnomad4 SAS AF: 0.708

Gnomad4 FIN AF: 0.757

Gnomad4 NFE AF: 0.682

Gnomad4 OTH AF: 0.641

Alfa AF: 0.663 Hom.: 16025

Bravo AF: 0.659

Asia WGS AF: 0.772 AC: 2686 AN: 3478

EpiCase AF: 0.674

EpiControl AF: 0.656

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 89% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 83. Only high quality variants are reported. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Migraine, familial hemiplegic, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Dec 31, 2015

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Severe myoclonic epilepsy in infancy Benign:1

Benign, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 21, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.5
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs7580482; hg19: chr2-166903445; COSMIC: COSV57690599;