rs121918817

Positions:

chr2-166045080-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001165963.4(SCN1A):c.1625G>A(p.Arg542Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,614,152 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 5 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.41

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 Benign. Variant got -12 ACMG points.

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). The gene has 848 curated pathogenic missense variants (we use a threshold of 10). The gene has 89 curated benign missense variants. GenCC has associacion of the 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=0.009377807).

BP6

Variant 2-166045080-C-T is Benign according to our data. Variant chr2-166045080-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68588.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_benign=4, not_provided=1, Benign=4}. Variant chr2-166045080-C-T is described in Lovd as [Benign]. Variant chr2-166045080-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00153 (233/152298) while in subpopulation NFE AF= 0.002 (136/68022). AF 95% confidence interval is 0.00173. There are 2 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 233 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4 link	c.1625G>A	p.Arg542Gln	missense_variant	13/29	ENST00000674923.1	NP_001159435.1	P35498-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN1A	ENST00000674923.1 link	c.1625G>A	p.Arg542Gln	missense_variant	13/29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 link	c.1625G>A	p.Arg542Gln	missense_variant	12/28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 link	c.1625G>A	p.Arg542Gln	missense_variant	10/26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.1 link	c.1625G>A	p.Arg542Gln	missense_variant	10/26	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

AF:

0.00153

AC:

233

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00200

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00170

AC:

427

AN:

251248

Hom.:

AF XY:

0.00163

AC XY:

222

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.0197

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00150

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00152

AC:

2216

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

1071

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.0204

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000545

Gnomad4 FIN exome

AF:

0.000468

Gnomad4 NFE exome

AF:

0.00129

Gnomad4 OTH exome

AF:

0.00209

GnomAD4 genome

AF:

0.00153

AC:

233

AN:

152298

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

106

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.0196

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00200

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00252

Hom.:

Bravo

AF:

0.00158

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00153

AC:

186

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00229

EpiControl

AF:

0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:12Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 09, 2022	Variant summary: SCN1A c.1625G>A (p.Arg542Gln) results in a conservative amino acid change in the encoded protein sequence. Three 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 251248 control chromosomes. The observed variant frequency is approximately 95 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 benign. Although reported in the literature, to our knowledge, no occurrence of c.1625G>A in individuals affected with SCN1A-Related Seizure Disorder and no conclusive experimental evidence demonstrating its impact on protein function have been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments but a predominant consensus as benign/likely benign (n=7). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SCN1A: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Self-limited epilepsy with centrotemporal spikes

Pathogenic:1

Pathogenic, flagged submission

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Autism

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

UniProtKB/Swiss-Prot

- -

Severe myoclonic epilepsy in infancy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Oct 04, 2019

PP3, BS2 -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2019

This alteration is classified as 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

SCN1A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2020

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). -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Epilepsy;C0751122:Severe myoclonic epilepsy in infancy

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

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

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.031

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.081

MetaRNN

Benign

0.0094

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

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

1.9

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

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.9

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

REVEL

Uncertain

0.31

Sift

Benign

0.048

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

Sift4G

Benign

0.15

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

Polyphen

0.42, 0.040

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

Vest4

0.23, 0.24, 0.25, 0.25

MVP

0.92

MPC

1.1

ClinPred

0.041

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.62

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