dbSNP rs121917910: SCN1A:p.Glu1308Asp (chr2-166009797-T-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_001165963.4(SCN1A):c.3924A>T(p.Glu1308Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000852 in 1,607,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1308K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00087 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:11O:1

Conservation

PhyloP100: 1.27

Publications

14 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 -10 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.057480246).

BP6

Variant 2-166009797-T-A is Benign according to our data. Variant chr2-166009797-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 68534.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000642 (97/151094) while in subpopulation NFE AF = 0.00116 (78/67298). AF 95% confidence interval is 0.000952. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 97 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165963.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN1A	NM_001165963.4	MANE Select	c.3924A>T	p.Glu1308Asp	missense	Exon 23 of 29	NP_001159435.1	P35498-1
SCN1A	NM_001202435.3		c.3924A>T	p.Glu1308Asp	missense	Exon 22 of 28	NP_001189364.1	P35498-1
SCN1A	NM_001353948.2		c.3924A>T	p.Glu1308Asp	missense	Exon 21 of 27	NP_001340877.1	P35498-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN1A	ENST00000674923.1	MANE Select	c.3924A>T	p.Glu1308Asp	missense	Exon 23 of 29	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9	TSL:5	c.3924A>T	p.Glu1308Asp	missense	Exon 22 of 28	ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7	TSL:5	c.3891A>T	p.Glu1297Asp	missense	Exon 20 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes

AF:

0.000642

AC:

AN:

150976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000265

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.000483

GnomAD2 exomes

AF:

0.000607

AC:

152

AN:

250236

AF XY:

0.000673

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.0000872

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000509

Gnomad NFE exome

AF:

0.00114

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000873

AC:

1272

AN:

1456390

Hom.:

Cov.:

AF XY:

0.000867

AC XY:

628

AN XY:

724606

show subpopulations

African (AFR)

AF:

0.0000602

AC:

AN:

33224

American (AMR)

AF:

0.000180

AC:

AN:

44506

Ashkenazi Jewish (ASJ)

AF:

0.000116

AC:

AN:

25906

East Asian (EAS)

AF:

0.00

AC:

AN:

39480

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86122

European-Finnish (FIN)

AF:

0.000787

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00105

AC:

1168

AN:

1108034

Other (OTH)

AF:

0.000766

AC:

AN:

60030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

112

169

225

281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

126

168

210

<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:

0.000642

AC:

AN:

151094

Hom.:

Cov.:

AF XY:

0.000528

AC XY:

AN XY:

73854

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41390

American (AMR)

AF:

0.000265

AC:

AN:

15108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3440

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000472

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00116

AC:

AN:

67298

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.000952

Hom.:

Bravo

AF:

0.000536

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000750

AC:

EpiCase

AF:

0.000820

EpiControl

AF:

0.00125

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (2)

Developmental and epileptic encephalopathy (1)

Generalized epilepsy with febrile seizures plus, type 2 (1)

Inborn genetic diseases (1)

Migraine, familial hemiplegic, 3 (1)

SCN1A-related disorder (1)

Severe myoclonic epilepsy in infancy (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Uncertain

0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

Eigen

Benign

-0.13

Eigen_PC

Benign

0.066

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.057

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

0.050

PhyloP100

1.3

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.50

Sift

Benign

0.28

Sift4G

Benign

0.68

Polyphen

0.047

Vest4

0.44

MutPred

0.47

Loss of loop (P = 0.0804)

MVP

0.95

MPC

0.71

ClinPred

0.060

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.88

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over