2-166048928-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Moderate

The NM_001165963.4(SCN1A):c.986G>A(p.Gly329Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G329A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.12

Publications

3 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: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001165963.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-166048928-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1032678.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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.865

PP5

Variant 2-166048928-C-T is Pathogenic according to our data. Variant chr2-166048928-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1483036.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4 link	c.986G>A	p.Gly329Asp	missense_variant	Exon 10 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SCN1A	ENST00000674923.1 link	c.986G>A	p.Gly329Asp	missense_variant	Exon 10 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9 link	c.986G>A	p.Gly329Asp	missense_variant	Exon 9 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7 link	c.986G>A	p.Gly329Asp	missense_variant	Exon 7 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2 link	c.986G>A	p.Gly329Asp	missense_variant	Exon 9 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250408

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453718

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723730

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33292

American (AMR)

AF:

0.00

AC:

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26004

East Asian (EAS)

AF:

0.00

AC:

AN:

39482

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86070

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105106

Other (OTH)

AF:

0.00

AC:

AN:

60058

⚠️ 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: 0.375

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

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Pathogenic:1

Sep 04, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. This variant disrupts the p.Gly329 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28084635; external communication). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces glycine with aspartic acid at codon 329 of the SCN1A protein (p.Gly329Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs779184118, ExAC 0.006%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

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

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.87

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

.;.;.;L;L;.;L;L;L;L

PhyloP100

4.1

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.4

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

REVEL

Pathogenic

0.81

Sift

Benign

0.030

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

Sift4G

Benign

0.086

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

Polyphen

1.0, 0.37

.;.;.;D;B;.;D;B;B;.

Vest4

0.87, 0.88, 0.87, 0.84

MutPred

0.61

Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);

MVP

0.97

MPC

2.0

ClinPred

0.99

GERP RS

5.3

Varity_R

0.59

gMVP

0.95

Mutation Taster

=0/100

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over