rs794727025

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP2PP3_ModeratePP5BS2

The NM_001165963.4(SCN1A):c.1703G>A(p.Arg568Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000743 in 1,614,136 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 4.88

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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 migraine, familial hemiplegic, 3, familial hemiplegic migraine, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, myoclonic-astatic epilepsy, developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 6, familial or sporadic hemiplegic migraine, arthrogryposis, Lennox-Gastaut syndrome, generalized epilepsy with febrile seizures plus, type 2.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

PP5

Variant 2-166044009-C-T is Pathogenic according to our data. Variant chr2-166044009-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193841.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4 link	c.1703G>A	p.Arg568Gln	missense_variant	Exon 14 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.1703G>A	p.Arg568Gln	missense_variant	Exon 14 of 29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 link	c.1703G>A	p.Arg568Gln	missense_variant	Exon 13 of 28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 link	c.1703G>A	p.Arg568Gln	missense_variant	Exon 11 of 26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.1 link	c.1703G>A	p.Arg568Gln	missense_variant	Exon 11 of 26	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251104

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135682

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Apr 18, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in two unrelated patients with epilepsy in published literature (Arafat et al., 2017; Butler et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This substitution is predicted to be in the cytoplasmic loop between the first and second homologous domains.; This variant is associated with the following publications: (PMID: 25348405, 18804930, 29056246, 28387369) -

Nov 16, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 568 of the SCN1A protein (p.Arg568Gln). This variant is present in population databases (rs794727025, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of autosomal dominant SCN1A-related conditions and/or clinical features of SCN1A-related conditions (PMID: 28387369, 29056246; internal data). ClinVar contains an entry for this variant (Variation ID: 193841). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

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

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.86

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

.;.;.;M;M;.;M;M;M;M

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.9

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

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

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

Sift4G

Benign

0.18

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

Polyphen

1.0, 1.0

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

Vest4

0.72, 0.66, 0.69, 0.62

MutPred

0.38

.;Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);Loss of methylation at R568 (P = 0.0152);

MVP

0.97

MPC

1.8

ClinPred

0.99

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over