rs121918799

Positions:

chr2-166015636-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM1PP2BP4_StrongBS2

The NM_001165963.4(SCN1A):c.3521C>G(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: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 11 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

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 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 made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 8 uncertain in NM_001165963.4

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.010132015).

BS2

High AC in GnomAd4 at 224 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4 linkuse as main transcript	c.3521C>G	p.Thr1174Ser	missense_variant	20/29	ENST00000674923.1
LOC102724058	NR_110598.1 linkuse as main transcript	n.199G>C		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1 linkuse as main transcript	c.3521C>G	p.Thr1174Ser	missense_variant	20/29		NM_001165963.4	P4	P35498-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.216G>C		non_coding_transcript_exon_variant	2/19

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

224

AN:

151852

Hom.:

Cov.:

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.:

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.:

Cov.:

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.:

Cov.:

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.:

Bravo

AF:

0.00114

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00177

AC:

215

Asia WGS

AF:

0.000289

AC:

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SCN1A: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2019	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 27, 2017	- -

Migraine, familial hemiplegic, 3

Uncertain:1Benign:1Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Uncertain significance. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 05, 2022	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 12, 2020	- -

Generalized epilepsy with febrile seizures plus, type 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 26, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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

not provided, no classification provided	literature only	Channelopathy-Associated Epilepsy Research Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

Childhood epilepsy with centrotemporal spikes

Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Seizure;C0494475:Bilateral tonic-clonic seizure;C4316903:Generalized non-motor (absence) seizure

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 13, 2014

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2018

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

SCN1A-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.34

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

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.14

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

M_CAP

Benign

0.038

MetaRNN

Benign

0.010

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

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.5

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

MutationTaster

Benign

0.78

N;N;N;N

PrimateAI

Benign

0.42

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

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.

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