NM_001165963.4:c.3521C>G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2BP4_StrongBS1BS2

The NM_001165963.4(SCN1A):ā€‹c.3521C>Gā€‹(p.Thr1174Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,612,736 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0015 ( 0 hom., cov: 32)
Exomes š‘“: 0.0016 ( 11 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:12O:2

Conservation

PhyloP100: 3.46
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-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.010132015).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00147 (224/151970) while in subpopulation NFE AF= 0.00234 (159/67844). AF 95% confidence interval is 0.00205. There are 0 homozygotes in gnomad4. There are 121 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 224 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN1ANM_001165963.4 linkc.3521C>G p.Thr1174Ser missense_variant Exon 20 of 29 ENST00000674923.1 NP_001159435.1 P35498-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN1AENST00000674923.1 linkc.3521C>G p.Thr1174Ser missense_variant Exon 20 of 29 NM_001165963.4 ENSP00000501589.1 P35498-1
SCN1AENST00000303395.9 linkc.3521C>G p.Thr1174Ser missense_variant Exon 19 of 28 5 ENSP00000303540.4 P35498-1
SCN1AENST00000375405.7 linkc.3488C>G p.Thr1163Ser missense_variant Exon 17 of 26 5 ENSP00000364554.3 P35498-2
SCN1AENST00000409050.1 linkc.3437C>G p.Thr1146Ser missense_variant Exon 17 of 26 5 ENSP00000386312.1 P35498-3

Frequencies

GnomAD3 genomes
AF:
0.00148
AC:
224
AN:
151852
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000314
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000657
Gnomad ASJ
AF:
0.000578
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00443
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00234
Gnomad OTH
AF:
0.000480
GnomAD3 exomes
AF:
0.00165
AC:
415
AN:
251166
Hom.:
3
AF XY:
0.00177
AC XY:
240
AN XY:
135746
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.000794
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00351
Gnomad NFE exome
AF:
0.00273
Gnomad OTH exome
AF:
0.000815
GnomAD4 exome
AF:
0.00165
AC:
2409
AN:
1460766
Hom.:
11
Cov.:
31
AF XY:
0.00169
AC XY:
1226
AN XY:
726646
show subpopulations
Gnomad4 AFR exome
AF:
0.000329
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.000729
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000232
Gnomad4 FIN exome
AF:
0.00344
Gnomad4 NFE exome
AF:
0.00188
Gnomad4 OTH exome
AF:
0.00136
GnomAD4 genome
AF:
0.00147
AC:
224
AN:
151970
Hom.:
0
Cov.:
32
AF XY:
0.00163
AC XY:
121
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.000313
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.000578
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00443
Gnomad4 NFE
AF:
0.00234
Gnomad4 OTH
AF:
0.000475
Alfa
AF:
0.00215
Hom.:
1
Bravo
AF:
0.00114
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.00130
AC:
5
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00163
AC:
14
ExAC
AF:
0.00177
AC:
215
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00196
EpiControl
AF:
0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3Benign:12Other:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
May 06, 2019
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24842605, 24679980, 22780858, 25576396, 24664660, 23801004, 23398611, 11254445, 22550089, 18021921, 21396429, 26990884, 27017028, 26763045, 26236192, 20301562, 31782251, 31765958) -

Dec 27, 2017
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SCN1A: BP4, BS1, BS2 -

Migraine, familial hemiplegic, 3 Uncertain:1Benign:1Other:1
-
UniProtKB/Swiss-Prot
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Jan 01, 2016
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Uncertain significance. -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:2
Oct 12, 2020
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 05, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: SCN1A c.3521C>G (p.Thr1174Ser) results in a conservative amino acid change located in the Sodium ion transport-associated domain (IPR010526) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251678 control chromosomes (gnomAD, Escayg_2001, Yordanova_2011, Cestele_2013), predominantly at a frequency of 0.0027 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 150-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN1A causing SCN1A-Related Seizure Disorder phenotype (1.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3521C>G has been reported in the literature but evidence does not allow for unequivocal conclusions regarding association of the variant with disease. Specifically, the variant was found to segregate with SCN1A-Related Seizure Disorder in some families (e.g. Cestele_2013, Lal_2016), while in other families it was found in affected probands who had inherited it from their unaffected parents or in families with some affected and some unaffected carriers (e.g. Yordanova_2011, LeGal_2014, Lal_2016, Till_2020). In addition, co-occurring pathogenic variants have been reported in multiple affected individuals (SCN1A c.3637C>T, p.Arg1213X; GRIN2B c.1619G>A, p.R540H; SCN1A c.4219C>T, p.Arg1407X; SCN1A c.3677delT, p.Phe1226SerfsX2) (Internal testing, Lal_2016, Till_2020), providing supporting evidence for a benign role. Functional effects were divergent: positive shift of the activation curve and deceleration of recovery from fast inactivation, consistent with loss of function, and increase of persistent current (INaP), consistent with gain of function (Cestele_2013). However, it is uncertain to what extent and if these findings correlate with actual disease manifestation. Twelve ClinVar submitters have assessed the variant since 2014: eight classified the variant as benign/likely benign, three as of uncertain significance and one as pathogenic. Based on the evidence outlined above, the variant was classified as benign. -

Generalized epilepsy with febrile seizures plus, type 2 Benign:2
Apr 26, 2022
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Severe myoclonic epilepsy in infancy Benign:1Other:1
Aug 22, 2023
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Channelopathy-Associated Epilepsy Research Center
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Self-limited epilepsy with centrotemporal spikes Pathogenic:1
Jan 01, 2017
Bioinformatics Core, Luxembourg Center for Systems Biomedicine
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: case-control

CAADphred>15 -

Seizure;C0494475:Bilateral tonic-clonic seizure;C4316903:Generalized non-motor (absence) seizure Uncertain:1
Nov 13, 2014
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Jul 17, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

SCN1A-related disorder Benign:1
Apr 29, 2021
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Epilepsy Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
21
DANN
Benign
0.79
DEOGEN2
Benign
0.34
.;.;.;T;.;.;T;.;.;.
Eigen
Benign
-0.46
Eigen_PC
Benign
-0.16
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.14
T;T;T;T;.;T;.;.;T;T
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.010
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
-1.5
.;.;.;N;.;.;N;.;.;.
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-0.21
.;.;.;N;.;.;N;.;N;N
REVEL
Uncertain
0.40
Sift
Benign
0.76
.;.;.;T;.;.;T;.;T;T
Sift4G
Benign
1.0
.;.;.;T;.;.;T;.;T;T
Polyphen
0.0
.;.;.;B;B;.;B;B;B;.
Vest4
0.48, 0.69, 0.55, 0.47
MutPred
0.29
.;Loss of glycosylation at T1174 (P = 0.0878);.;Loss of glycosylation at T1174 (P = 0.0878);.;.;Loss of glycosylation at T1174 (P = 0.0878);.;.;.;
MVP
0.85
MPC
0.64
ClinPred
0.021
T
GERP RS
5.4
Varity_R
0.13
gMVP
0.50

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: rs121918799; hg19: chr2-166872146; API