rs184524479

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001165963.4(SCN1A):ā€‹c.1604G>Cā€‹(p.Arg535Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R535C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

11
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.48
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN1A. . Gene score misZ 5.2206 (greater than the threshold 3.09). Trascript score misZ 7.6022 (greater than threshold 3.09). GenCC has associacion of gene with 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN1ANM_001165963.4 linkuse as main transcriptc.1604G>C p.Arg535Pro missense_variant 13/29 ENST00000674923.1 NP_001159435.1 P35498-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN1AENST00000674923.1 linkuse as main transcriptc.1604G>C p.Arg535Pro missense_variant 13/29 NM_001165963.4 ENSP00000501589.1 P35498-1
SCN1AENST00000303395.9 linkuse as main transcriptc.1604G>C p.Arg535Pro missense_variant 12/285 ENSP00000303540.4 P35498-1
SCN1AENST00000375405.7 linkuse as main transcriptc.1604G>C p.Arg535Pro missense_variant 10/265 ENSP00000364554.3 P35498-2
SCN1AENST00000409050.1 linkuse as main transcriptc.1604G>C p.Arg535Pro missense_variant 10/265 ENSP00000386312.1 P35498-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251334
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135844
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 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:
0.00000205
AC:
3
AN:
1461870
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 25, 2021This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SCN1A-related conditions. This sequence change replaces arginine with proline at codon 535 of the SCN1A protein (p.Arg535Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.39
BayesDel_addAF
Uncertain
0.039
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.77
.;.;.;D;.;.;D;.;.;.
Eigen
Benign
-0.026
Eigen_PC
Benign
0.11
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.84
T;T;T;T;.;T;.;.;T;T
M_CAP
Benign
0.061
D
MetaRNN
Uncertain
0.46
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.61
T
MutationAssessor
Uncertain
2.3
.;.;.;M;M;.;M;M;M;M
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-4.1
.;.;.;D;.;.;D;.;D;D
REVEL
Uncertain
0.30
Sift
Uncertain
0.0060
.;.;.;D;.;.;D;.;D;D
Sift4G
Benign
0.079
.;.;.;T;.;.;T;.;T;T
Polyphen
0.10, 0.010
.;.;.;B;B;.;B;B;B;.
Vest4
0.33, 0.36, 0.34, 0.34
MutPred
0.40
.;Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);
MVP
0.57
MPC
2.0
ClinPred
0.96
D
GERP RS
4.3
Varity_R
0.80
gMVP
0.75

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

LitVar

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

Other links and lift over

dbSNP: rs184524479; hg19: chr2-166901611; API