rs138231868

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: This is a missense variant in SCN1A, c.4393A>G, (p.Ile1465Val). This variant is present in gnomAD at 0.04% within the total population, with the highest sub-population frequency of 0.4% within the African/African population American population (BA1). In summary, this variant meets criteria to be classified as benign for autosomal dominant dravet syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1 (version 1.0; approved 6/13/23). LINK:https://erepo.genome.network/evrepo/ui/classification/CA295639/MONDO:0100135/067

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: 4.85

Publications

5 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:

LOC102724058 (HGNC:):

LOC102724058 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4 link	c.4393A>G	p.Ile1465Val	missense_variant	Exon 26 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.4393A>G	p.Ile1465Val	missense_variant	Exon 26 of 29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 link	c.4393A>G	p.Ile1465Val	missense_variant	Exon 25 of 28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 link	c.4360A>G	p.Ile1454Val	missense_variant	Exon 23 of 26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.2 link	c.4309A>G	p.Ile1437Val	missense_variant	Exon 25 of 28	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

AF:

0.00111

AC:

167

AN:

151022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00397

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000273

AC:

AN:

249444

AF XY:

0.000222

show subpopulations

Gnomad AFR exome

AF:

0.00385

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000113

AC:

164

AN:

1454830

Hom.:

Cov.:

AF XY:

0.0000967

AC XY:

AN XY:

723888

show subpopulations

African (AFR)

AF:

0.00455

AC:

151

AN:

33196

American (AMR)

AF:

0.000112

AC:

AN:

44458

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25862

East Asian (EAS)

AF:

0.00

AC:

AN:

39416

South Asian (SAS)

AF:

0.00

AC:

AN:

85840

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107054

Other (OTH)

AF:

0.000133

AC:

AN:

59996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00110

AC:

167

AN:

151140

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

73816

show subpopulations

African (AFR)

AF:

0.00396

AC:

164

AN:

41402

American (AMR)

AF:

0.000132

AC:

AN:

15134

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3446

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67342

Other (OTH)

AF:

0.00

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000315

Hom.:

Bravo

AF:

0.00125

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000371

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 03, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 07, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Feb 05, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Developmental and epileptic encephalopathy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Severe myoclonic epilepsy in infancy

Benign:1

May 09, 2024

ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

This is a missense variant in SCN1A, c.4393A>G, (p.Ile1465Val). This variant is present in gnomAD at 0.04% within the total population, with the highest sub-population frequency of 0.4% within the African/African population American population (BA1). In summary, this variant meets criteria to be classified as benign for autosomal dominant dravet syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1 (version 1.0; approved 6/13/23). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

.;.;.;D;.;.;D;.;.;.

Eigen

Benign

0.033

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.76

T;T;T;T;.;T;.;.;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.013

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

0.51

.;.;.;N;.;.;N;.;.;.

PhyloP100

4.9

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.44

.;.;.;N;.;.;N;.;N;N

REVEL

Uncertain

0.44

Sift

Benign

0.23

.;.;.;T;.;.;T;.;T;T

Sift4G

Benign

0.47

.;.;.;T;.;.;T;.;T;T

Polyphen

0.085, 0.92

.;.;.;B;P;.;B;P;P;.

Vest4

0.34, 0.41, 0.42, 0.39

MVP

0.42

MPC

0.72

ClinPred

0.059

GERP RS

5.3

Varity_R

0.15

gMVP

0.87

Mutation Taster

=13/87

disease causing

(source)

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

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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