2-166073486-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1PP2BS2

The NM_001165963.4(SCN1A):c.136G>A(p.Glu46Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000378 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.78

Publications

7 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: Likely_benign. The variant received -1 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 127) in uniprot entity SCN1A_HUMAN there are 60 pathogenic changes around while only 7 benign (90%) in NM_001165963.4

PP2

Missense variant in the SCN1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 848 curated pathogenic missense variants (we use a threshold of 10). The gene has 89 curated benign missense variants. Gene score misZ: 5.2206 (above the threshold of 3.09). Trascript score misZ: 7.6022 (above the threshold of 3.09). GenCC associations: The gene is linked to familial or sporadic hemiplegic migraine, myoclonic-astatic epilepsy, arthrogryposis, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, type 2, migraine, familial hemiplegic, 3, developmental and epileptic encephalopathy, 6A, familial hemiplegic migraine, generalized epilepsy with febrile seizures plus, genetic developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.

BS2

High AC in GnomAdExome4 at 57 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4 link	c.136G>A	p.Glu46Lys	missense_variant	Exon 4 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.136G>A	p.Glu46Lys	missense_variant	Exon 4 of 29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 link	c.136G>A	p.Glu46Lys	missense_variant	Exon 3 of 28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 link	c.136G>A	p.Glu46Lys	missense_variant	Exon 1 of 26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.2 link	c.136G>A	p.Glu46Lys	missense_variant	Exon 3 of 28	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251448

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000162

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000360

AC:

AN:

1111998

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41444

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 13, 2016

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy

Uncertain:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 46 of the SCN1A protein (p.Glu46Lys). This variant is present in population databases (rs769582667, gnomAD 0.02%). This missense change has been observed in individual(s) with seizures (PMID: 37209046; internal data). ClinVar contains an entry for this variant (Variation ID: 448247). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN1A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Generalized epilepsy with febrile seizures plus, type 2

Uncertain:1

Lifecell International Pvt. Ltd

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous missense variant (c.136G>A) in exon 4 of the SCN1A gene that results in the amino acid substitution from Glutamic acid to Lysine at codon 46 (p.Glu46Lys) was identified. The observed variant has a minor allele frequency of 0.0028% in gnomAD database and not reported in 1000 genome database. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. The Missense Variants Z-Score for this variant is 5.28. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. (DOI: 10.1038/nature19057). The MPC score for this variant is 0.98. MPC score is computed on an analysis of the ExAC population frequencies, the Missense Badness Score is the normalized fold difference of observed versus expected missense substitutions in sub-genic regions. This score is then combined with orthogonal deleteriousness metrics into one score called MPC (for Missense badness, PolyPhen-2, and Constraint) designed to classify whether a missense variant is deleterious. (DOI: 10.1101/148353). Based on the above evidence this variant has been classified as variant of uncertain significance according to the ACMG guidelines. -

not provided

Uncertain:1

Aug 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

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

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

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

M_CAP

Uncertain

0.098

MetaRNN

Uncertain

0.58

D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

3.0

.;.;.;M;M;.;M;M;M;M

PhyloP100

4.8

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.7

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

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0030

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

Sift4G

Benign

0.069

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

Polyphen

0.94

.;.;.;.;P;.;.;P;P;.

Vest4

0.55, 0.67, 0.70, 0.69

MutPred

0.35

Gain of methylation at E46 (P = 0.0141);Gain of methylation at E46 (P = 0.0141);Gain of methylation at E46 (P = 0.0141);Gain of methylation at E46 (P = 0.0141);Gain of methylation at E46 (P = 0.0141);Gain of methylation at E46 (P = 0.0141);Gain of methylation at E46 (P = 0.0141);Gain of methylation at E46 (P = 0.0141);Gain of methylation at E46 (P = 0.0141);Gain of methylation at E46 (P = 0.0141);

MVP

0.97

MPC

0.98

ClinPred

0.34

GERP RS

5.1

PromoterAI

0.016

Neutral

(source)

Varity_R

0.30

gMVP

0.75

Mutation Taster

=14/86

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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2-166073486-C-T

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