rs7580482

Positions:

chr2-166046935-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001165963.4(SCN1A):c.1212A>G(p.Val404=) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V404V?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.67 ( 34209 hom., cov: 32)

Exomes 𝑓: 0.70 ( 355737 hom. )

Consequence

SCN1A
NM_001165963.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.280

Variant links:

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 links:

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

SCN1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	UniProt
SCN1A	NM_001165963.4 linkuse as main transcript	c.1212A>G	p.Val404=	synonymous_variant	12/29	ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1 linkuse as main transcript	c.1212A>G	p.Val404=	synonymous_variant	12/29		NM_001165963.4	P4	P35498-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.487+10805T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.667

AC:

101261

AN:

151924

Hom.:

34181

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.693

AC XY:

503895

AN XY:

727034

show subpopulations

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.:

AF XY:

0.672

AC XY:

49971

AN XY:

74326

show subpopulations

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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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	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. -
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	-	- -

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

Invitae

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

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 15, 2017

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

- -

Epilepsy

Benign:1

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

-0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over