dbSNP rs146878122: SCN1A:p.Thr1300Ile (chr2-166009822-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 5P and 7B. PM1PM5PP2BP4_ModerateBP6BS2

The NM_001165963.4(SCN1A):c.3899C>T(p.Thr1300Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000996 in 1,606,822 control chromosomes in the GnomAD database, including 1 homozygotes. 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. T1300R) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 1 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 5.18

Publications

4 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: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_001165963.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-166009822-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 189968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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=0.107675105).

BP6

Variant 2-166009822-G-A is Benign according to our data. Variant chr2-166009822-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206812.

BS2

High AC in GnomAd4 at 29 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
SCN1A	NM_001165963.4	MANE Select	c.3899C>T	p.Thr1300Ile	missense	Exon 23 of 29	NP_001159435.1
SCN1A	NM_001202435.3		c.3899C>T	p.Thr1300Ile	missense	Exon 22 of 28	NP_001189364.1
SCN1A	NM_001353948.2		c.3899C>T	p.Thr1300Ile	missense	Exon 21 of 27	NP_001340877.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN1A	ENST00000674923.1	MANE Select	c.3899C>T	p.Thr1300Ile	missense	Exon 23 of 29	ENSP00000501589.1
SCN1A	ENST00000303395.9	TSL:5	c.3899C>T	p.Thr1300Ile	missense	Exon 22 of 28	ENSP00000303540.4
SCN1A	ENST00000375405.7	TSL:5	c.3866C>T	p.Thr1289Ile	missense	Exon 20 of 26	ENSP00000364554.3

Frequencies

GnomAD3 genomes

AF:

0.000192

AC:

AN:

150880

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000664

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000892

Gnomad OTH

AF:

0.00145

GnomAD2 exomes

AF:

0.000156

AC:

AN:

250156

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000465

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000900

AC:

131

AN:

1455826

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

724346

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33198

American (AMR)

AF:

0.000539

AC:

AN:

44492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25896

East Asian (EAS)

AF:

0.00

AC:

AN:

39468

South Asian (SAS)

AF:

0.0000929

AC:

AN:

86128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.000874

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.0000713

AC:

AN:

1107620

Other (OTH)

AF:

0.000183

AC:

AN:

59970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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:

0.000192

AC:

AN:

150996

Hom.:

Cov.:

AF XY:

0.000230

AC XY:

AN XY:

73778

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41368

American (AMR)

AF:

0.000663

AC:

AN:

15080

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.00

AC:

AN:

5130

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000892

AC:

AN:

67288

Other (OTH)

AF:

0.00144

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.0000649

Hom.:

Bravo

AF:

0.000298

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000219

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Developmental and epileptic encephalopathy (1)

Inborn genetic diseases (1)

Intellectual disability (1)

Severe myoclonic epilepsy in infancy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Benign

0.90

DEOGEN2

Uncertain

0.61

Eigen

Benign

0.014

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.11

MetaSVM

Uncertain

0.79

MutationAssessor

Benign

-0.41

PhyloP100

5.2

PrimateAI

Uncertain

0.78

PROVEAN

Benign

1.7

REVEL

Uncertain

0.42

Sift

Benign

0.35

Sift4G

Benign

0.68

Polyphen

0.050

Vest4

0.44

MVP

0.61

MPC

0.80

ClinPred

0.064

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.90

Mutation Taster

=6/94

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over