Genetic Variant SCN1A:c.384-20G>C (chr2-166056520-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001165963.4(SCN1A):c.384-20G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00668 in 1,509,564 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0067 ( 60 hom. )

Consequence

SCN1A
NM_001165963.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.242

Publications

1 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 2-166056520-C-G is Benign according to our data. Variant chr2-166056520-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00612 (931/152074) while in subpopulation NFE AF = 0.00733 (498/67948). AF 95% confidence interval is 0.0068. There are 5 homozygotes in GnomAd4. There are 523 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 931 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	Effect	Exon Rank	Protein	UniProt
SCN1A	NM_001165963.4	MANE Select	c.384-20G>C	intron	N/A	NP_001159435.1	P35498-1
SCN1A	NM_001202435.3		c.384-20G>C	intron	N/A	NP_001189364.1	P35498-1
SCN1A	NM_001353948.2		c.384-20G>C	intron	N/A	NP_001340877.1	P35498-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SCN1A	ENST00000674923.1	MANE Select	c.384-20G>C	intron	N/A	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9	TSL:5	c.384-20G>C	intron	N/A	ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7	TSL:5	c.384-20G>C	intron	N/A	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes

AF:

0.00613

AC:

931

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00217

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.0279

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00733

Gnomad OTH

AF:

0.00528

GnomAD2 exomes

AF:

0.00617

AC:

1541

AN:

249896

AF XY:

0.00617

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.000784

Gnomad ASJ exome

AF:

0.00668

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0254

Gnomad NFE exome

AF:

0.00692

Gnomad OTH exome

AF:

0.00872

GnomAD4 exome

AF:

0.00674

AC:

9146

AN:

1357490

Hom.:

Cov.:

AF XY:

0.00661

AC XY:

4503

AN XY:

681718

show subpopulations

African (AFR)

AF:

0.000800

AC:

AN:

31262

American (AMR)

AF:

0.000899

AC:

AN:

44508

Ashkenazi Jewish (ASJ)

AF:

0.00826

AC:

210

AN:

25438

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39088

South Asian (SAS)

AF:

0.00182

AC:

153

AN:

83916

European-Finnish (FIN)

AF:

0.0251

AC:

1339

AN:

53320

Middle Eastern (MID)

AF:

0.00287

AC:

AN:

5568

European-Non Finnish (NFE)

AF:

0.00694

AC:

7057

AN:

1017478

Other (OTH)

AF:

0.00536

AC:

305

AN:

56912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

405

809

1214

1618

2023

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

266

532

798

1064

1330

<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:

0.00612

AC:

931

AN:

152074

Hom.:

Cov.:

AF XY:

0.00704

AC XY:

523

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

41516

American (AMR)

AF:

0.00217

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00373

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0279

AC:

295

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00733

AC:

498

AN:

67948

Other (OTH)

AF:

0.00522

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

140

186

233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00635

Hom.:

Bravo

AF:

0.00378

Asia WGS

AF:

0.00173

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

Developmental and epileptic encephalopathy (1)

SCN1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

6.4

(source)

DANN

Benign

0.66

PhyloP100

-0.24

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over