rs6432860

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001165963.4(SCN1A):c.2292T>C(p.Val764Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 1,613,016 control chromosomes in the GnomAD database, including 404,607 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. V764V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.74 ( 41728 hom., cov: 30)

Exomes 𝑓: 0.70 ( 362879 hom. )

Consequence

SCN1A
NM_001165963.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -0.608

Publications

53 publications found

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 was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 2-166041354-A-G is Benign according to our data. Variant chr2-166041354-A-G is described in ClinVar as Benign. ClinVar VariationId is 36752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.608 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 rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4 link	c.2292T>C	p.Val764Val	synonymous_variant	Exon 16 of 29	ENST00000674923.1	NP_001159435.1	P35498-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN1A	ENST00000674923.1 link	c.2292T>C	p.Val764Val	synonymous_variant	Exon 16 of 29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 link	c.2292T>C	p.Val764Val	synonymous_variant	Exon 15 of 28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 link	c.2259T>C	p.Val753Val	synonymous_variant	Exon 13 of 26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.2 link	c.2208T>C	p.Val736Val	synonymous_variant	Exon 15 of 28	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

AF:

0.737

AC:

111953

AN:

151804

Hom.:

41683

Cov.:

show subpopulations

Gnomad AFR

AF:

0.824

Gnomad AMI

AF:

0.645

Gnomad AMR

AF:

0.742

Gnomad ASJ

AF:

0.602

Gnomad EAS

AF:

0.891

Gnomad SAS

AF:

0.709

Gnomad FIN

AF:

0.755

Gnomad MID

AF:

0.525

Gnomad NFE

AF:

0.683

Gnomad OTH

AF:

0.679

GnomAD2 exomes

AF:

0.726

AC:

182465

AN:

251300

AF XY:

0.715

show subpopulations

Gnomad AFR exome

AF:

0.830

Gnomad AMR exome

AF:

0.809

Gnomad ASJ exome

AF:

0.599

Gnomad EAS exome

AF:

0.896

Gnomad FIN exome

AF:

0.745

Gnomad NFE exome

AF:

0.679

Gnomad OTH exome

AF:

0.677

GnomAD4 exome

AF:

0.703

AC:

1026435

AN:

1461094

Hom.:

362879

Cov.:

AF XY:

0.699

AC XY:

508089

AN XY:

726928

show subpopulations

African (AFR)

AF:

0.827

AC:

27688

AN:

33472

American (AMR)

AF:

0.803

AC:

35893

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.601

AC:

15710

AN:

26126

East Asian (EAS)

AF:

0.895

AC:

35526

AN:

39680

South Asian (SAS)

AF:

0.683

AC:

58908

AN:

86238

European-Finnish (FIN)

AF:

0.748

AC:

39968

AN:

53414

Middle Eastern (MID)

AF:

0.512

AC:

2942

AN:

5748

European-Non Finnish (NFE)

AF:

0.691

AC:

767795

AN:

1111334

Other (OTH)

AF:

0.696

AC:

42005

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

15017

30034

45051

60068

75085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19682

39364

59046

78728

98410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.738

AC:

112059

AN:

151922

Hom.:

41728

Cov.:

AF XY:

0.741

AC XY:

55013

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.823

AC:

34126

AN:

41442

American (AMR)

AF:

0.743

AC:

11338

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.602

AC:

2090

AN:

3470

East Asian (EAS)

AF:

0.891

AC:

4606

AN:

5168

South Asian (SAS)

AF:

0.709

AC:

3414

AN:

4812

European-Finnish (FIN)

AF:

0.755

AC:

7968

AN:

10550

Middle Eastern (MID)

AF:

0.520

AC:

153

AN:

294

European-Non Finnish (NFE)

AF:

0.682

AC:

46340

AN:

67898

Other (OTH)

AF:

0.682

AC:

1436

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1432

2864

4295

5727

7159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

846

1692

2538

3384

4230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.703

Hom.:

76350

Bravo

AF:

0.741

Asia WGS

AF:

0.790

AC:

2745

AN:

3476

EpiCase

AF:

0.674

EpiControl

AF:

0.656

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Feb 12, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 11, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 90% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 84. Only high quality variants are reported. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Migraine, familial hemiplegic, 3

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Dec 31, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Developmental and epileptic encephalopathy

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Generalized epilepsy with febrile seizures plus

Benign:1

Aug 21, 2011

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Generalized epilepsy with febrile seizures plus, type 2

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Epilepsy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.43

(source)

DANN

Benign

0.61

PhyloP100

-0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over