2-166042428-TA-TAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001165963.4(SCN1A):c.2044-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000601 in 1,580,304 control chromosomes in the GnomAD database, including 7 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00031 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00063 ( 6 hom. )

Consequence

SCN1A
NM_001165963.4 splice_region, intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: -0.278

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 -9 ACMG points.

BP6

Variant 2-166042428-T-TA is Benign according to our data. Variant chr2-166042428-T-TA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194032.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000311 (47/151226) while in subpopulation SAS AF = 0.00417 (20/4792). AF 95% confidence interval is 0.00277. There are 1 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 47 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
SCN1A	NM_001165963.4	MANE Select	c.2044-5dupT	splice_region intron	N/A	NP_001159435.1
SCN1A	NM_001202435.3		c.2044-5dupT	splice_region intron	N/A	NP_001189364.1
SCN1A	NM_001353948.2		c.2044-5dupT	splice_region intron	N/A	NP_001340877.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SCN1A	ENST00000674923.1	MANE Select	c.2044-5_2044-4insT	splice_region intron	N/A	ENSP00000501589.1
SCN1A	ENST00000303395.9	TSL:5	c.2044-5_2044-4insT	splice_region intron	N/A	ENSP00000303540.4
SCN1A	ENST00000375405.7	TSL:5	c.2011-5_2011-4insT	splice_region intron	N/A	ENSP00000364554.3

Frequencies

GnomAD3 genomes

AF:

0.000311

AC:

AN:

151114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000198

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000775

Gnomad SAS

AF:

0.00417

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00101

AC:

231

AN:

228492

AF XY:

0.00130

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000163

Gnomad ASJ exome

AF:

0.000215

Gnomad EAS exome

AF:

0.000538

Gnomad FIN exome

AF:

0.000207

Gnomad NFE exome

AF:

0.000269

Gnomad OTH exome

AF:

0.000540

GnomAD4 exome

AF:

0.000631

AC:

902

AN:

1429078

Hom.:

Cov.:

AF XY:

0.000756

AC XY:

538

AN XY:

711340

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000428

AC:

AN:

32704

American (AMR)

AF:

0.000182

AC:

AN:

43998

Ashkenazi Jewish (ASJ)

AF:

0.0000785

AC:

AN:

25468

East Asian (EAS)

AF:

0.000389

AC:

AN:

38562

South Asian (SAS)

AF:

0.00548

AC:

466

AN:

85054

European-Finnish (FIN)

AF:

0.000154

AC:

AN:

51936

Middle Eastern (MID)

AF:

0.000355

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

0.000324

AC:

352

AN:

1086722

Other (OTH)

AF:

0.000593

AC:

AN:

59004

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.398

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.000311

AC:

AN:

151226

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

AN XY:

73892

show subpopulations

African (AFR)

AF:

0.000218

AC:

AN:

41250

American (AMR)

AF:

0.000198

AC:

AN:

15164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.000777

AC:

AN:

5148

South Asian (SAS)

AF:

0.00417

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

67734

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000400

Hom.:

Bravo

AF:

0.000200

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Developmental and epileptic encephalopathy (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.28

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over