2-166036278-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001165963.4(SCN1A):c.3199G>A(p.Ala1067Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 1,613,022 control chromosomes in the GnomAD database, including 404,559 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.74 ( 41764 hom., cov: 32)

Exomes 𝑓: 0.70 ( 362795 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.310

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 -19 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=7.491045E-7).

BP6

Variant 2-166036278-C-T is Benign according to our data. Variant chr2-166036278-C-T is described in ClinVar as [Benign]. Clinvar id is 36753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166036278-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4 link	c.3199G>A	p.Ala1067Thr	missense_variant	Exon 19 of 29	ENST00000674923.1	NP_001159435.1	P35498-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN1A	ENST00000674923.1 link	c.3199G>A	p.Ala1067Thr	missense_variant	Exon 19 of 29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 link	c.3199G>A	p.Ala1067Thr	missense_variant	Exon 18 of 28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 link	c.3166G>A	p.Ala1056Thr	missense_variant	Exon 16 of 26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.1 link	c.3115G>A	p.Ala1039Thr	missense_variant	Exon 16 of 26	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

AF:

0.737

AC:

112081

AN:

152006

Hom.:

41719

Cov.:

show subpopulations

Gnomad AFR

AF:

0.823

Gnomad AMI

AF:

0.645

Gnomad AMR

AF:

0.741

Gnomad ASJ

AF:

0.603

Gnomad EAS

AF:

0.891

Gnomad SAS

AF:

0.709

Gnomad FIN

AF:

0.756

Gnomad MID

AF:

0.525

Gnomad NFE

AF:

0.683

Gnomad OTH

AF:

0.681

GnomAD3 exomes

AF:

0.726

AC:

181805

AN:

250522

Hom.:

66920

AF XY:

0.715

AC XY:

96807

AN XY:

135400

show subpopulations

Gnomad AFR exome

AF:

0.829

Gnomad AMR exome

AF:

0.809

Gnomad ASJ exome

AF:

0.599

Gnomad EAS exome

AF:

0.896

Gnomad SAS exome

AF:

0.686

Gnomad FIN exome

AF:

0.745

Gnomad NFE exome

AF:

0.679

Gnomad OTH exome

AF:

0.676

GnomAD4 exome

AF:

0.702

AC:

1026255

AN:

1460898

Hom.:

362795

Cov.:

AF XY:

0.699

AC XY:

507991

AN XY:

726822

show subpopulations

Gnomad4 AFR exome

AF:

0.827

Gnomad4 AMR exome

AF:

0.803

Gnomad4 ASJ exome

AF:

0.601

Gnomad4 EAS exome

AF:

0.895

Gnomad4 SAS exome

AF:

0.683

Gnomad4 FIN exome

AF:

0.748

Gnomad4 NFE exome

AF:

0.691

Gnomad4 OTH exome

AF:

0.696

GnomAD4 genome

AF:

0.737

AC:

112187

AN:

152124

Hom.:

41764

Cov.:

AF XY:

0.741

AC XY:

55088

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.823

Gnomad4 AMR

AF:

0.742

Gnomad4 ASJ

AF:

0.603

Gnomad4 EAS

AF:

0.891

Gnomad4 SAS

AF:

0.709

Gnomad4 FIN

AF:

0.756

Gnomad4 NFE

AF:

0.682

Gnomad4 OTH

AF:

0.684

Alfa

AF:

0.688

Hom.:

45422

Bravo

AF:

0.740

TwinsUK

AF:

0.704

AC:

2611

ALSPAC

AF:

0.690

AC:

2658

ESP6500AA

AF:

0.816

AC:

3597

ESP6500EA

AF:

0.675

AC:

5809

ExAC

AF:

0.725

AC:

88032

Asia WGS

AF:

0.790

AC:

2743

AN:

3474

EpiCase

AF:

0.674

EpiControl

AF:

0.655

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jan 31, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 89% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 83. Only high quality variants are reported. -

not provided

Benign:2

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Migraine, familial hemiplegic, 3

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases

Benign:1

Dec 31, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Generalized epilepsy with febrile seizures plus

Benign:1

Aug 21, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Generalized epilepsy with febrile seizures plus, type 2

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Epilepsy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.38

CADD

Benign

2.4

DANN

Benign

0.80

DEOGEN2

Benign

0.36

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

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0054

LIST_S2

Benign

0.054

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

MetaRNN

Benign

7.5e-7

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

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.49

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

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.070

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

REVEL

Benign

0.27

Sift

Benign

0.64

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

Sift4G

Benign

0.56

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

Polyphen

0.0

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

Vest4

0.034, 0.029, 0.035, 0.043

MPC

0.70

ClinPred

0.0066

GERP RS

-2.9

Varity_R

0.11

gMVP

0.28

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