rs121917910

Positions:

chr2-166009797-T-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_001165963.4(SCN1A):c.3924A>T(p.Glu1308Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000852 in 1,607,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00087 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:11O:1

Conservation

PhyloP100: 1.27

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 Benign. Variant got -8 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). 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=0.057480246).

BP6

Variant 2-166009797-T-A is Benign according to our data. Variant chr2-166009797-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68534.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, not_provided=1, Benign=3, Uncertain_significance=3}. Variant chr2-166009797-T-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 97 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4 linkuse as main transcript	c.3924A>T	p.Glu1308Asp	missense_variant	23/29	ENST00000674923.1	NP_001159435.1
LOC102724058	NR_110598.1 linkuse as main transcript	n.176-5816T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1 linkuse as main transcript	c.3924A>T	p.Glu1308Asp	missense_variant	23/29		NM_001165963.4	ENSP00000501589	P4	P35498-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.193-5816T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000642

AC:

AN:

150976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000265

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.000483

GnomAD3 exomes

AF:

0.000607

AC:

152

AN:

250236

Hom.:

AF XY:

0.000673

AC XY:

AN XY:

135242

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.0000872

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000509

Gnomad NFE exome

AF:

0.00114

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000873

AC:

1272

AN:

1456390

Hom.:

Cov.:

AF XY:

0.000867

AC XY:

628

AN XY:

724606

show subpopulations

Gnomad4 AFR exome

AF:

0.0000602

Gnomad4 AMR exome

AF:

0.000180

Gnomad4 ASJ exome

AF:

0.000116

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000787

Gnomad4 NFE exome

AF:

0.00105

Gnomad4 OTH exome

AF:

0.000766

GnomAD4 genome

AF:

0.000642

AC:

AN:

151094

Hom.:

Cov.:

AF XY:

0.000528

AC XY:

AN XY:

73854

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000265

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000952

Hom.:

Bravo

AF:

0.000536

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000750

AC:

EpiCase

AF:

0.000820

EpiControl

AF:

0.00125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:11Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2019	This variant is associated with the following publications: (PMID: 20729507, 18930999, 19522081, 28717674, 27881154, 26990884, 31765958, 32090326) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2014	- -
Likely 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	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SCN1A: PP3, BS1, BS2 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 03, 2019	- -

Severe myoclonic epilepsy in infancy

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Migraine, familial hemiplegic, 3

Uncertain:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Generalized epilepsy with febrile seizures plus, type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

SCN1A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Uncertain

0.10

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

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

Eigen

Benign

-0.13

Eigen_PC

Benign

0.066

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.87

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

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.057

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

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

0.050

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.3

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

REVEL

Uncertain

0.50

Sift

Benign

0.28

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

Sift4G

Benign

0.68

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

Polyphen

0.047, 0.96

.;.;.;B;D;.;B;D;D;.

Vest4

0.44, 0.43, 0.46, 0.40

MutPred

0.47

.;Loss of loop (P = 0.0804);.;Loss of loop (P = 0.0804);.;.;Loss of loop (P = 0.0804);.;.;.;

MVP

0.95

MPC

0.71

ClinPred

0.060

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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