rs760676898

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001165963.4(SCN1A):c.5882T>C(p.Ile1961Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1961V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.19

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.22514677).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4 link	c.5882T>C	p.Ile1961Thr	missense_variant	Exon 29 of 29	ENST00000674923.1	NP_001159435.1	P35498-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN1A	ENST00000674923.1 link	c.5882T>C	p.Ile1961Thr	missense_variant	Exon 29 of 29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 link	c.5882T>C	p.Ile1961Thr	missense_variant	Exon 28 of 28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 link	c.5849T>C	p.Ile1950Thr	missense_variant	Exon 26 of 26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.2 link	c.5798T>C	p.Ile1933Thr	missense_variant	Exon 28 of 28	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250720

AF XY:

0.00000738

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:

6.84e-7

AC:

AN:

1461536

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727058

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111828

Other (OTH)

AF:

0.00

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Uncertain:1

Sep 25, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine with threonine at codon 1961 of the SCN1A protein (p.Ile1961Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs760676898, ExAC 0.006%). This variant has not been reported in the literature in individuals with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 206884). 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 not expected to disrupt SCN1A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Generalized epilepsy with febrile seizures plus, type 2

Uncertain:1

Feb 23, 2018

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing;provider interpretation

This variant was identified in an 11 year old female with autism spectrum disorder, global developmental delay, microcephaly, coordination disorder, a single seizure, imperforate anus, intermittent exotropia, and history of hydronephrosis. Initial EEG at age 3 was normal; EEG at age 4 following a single unprovoked seizure showed biposterior slowing. There is no paternal history of developmental delays or seizures. The variant is present in the gnomAD South Asian population at 0.0032%. Computational prediction models are inconsistent. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Uncertain

0.46

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

Eigen

Benign

-0.11

Eigen_PC

Benign

0.097

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.69

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

M_CAP

Benign

0.075

MetaRNN

Benign

0.23

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.31

MutationAssessor

Benign

0.13

.;.;.;N;.;N;.;.;.

PhyloP100

3.2

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.1

.;.;.;N;.;N;.;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.11

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

Sift4G

Benign

0.60

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

Polyphen

0.018

.;.;.;.;B;.;B;B;.

Vest4

0.16, 0.15, 0.14, 0.24

MutPred

0.52

.;.;.;Loss of stability (P = 0.0012);.;Loss of stability (P = 0.0012);.;.;.;

MVP

0.17

MPC

0.91

ClinPred

0.18

GERP RS

5.7

Varity_R

0.17

gMVP

0.33

Mutation Taster

=46/54

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over