2-166058574-G-C

Position:

chr2-166058574-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PM5PP2PP3_ModerateBP6BS2

The NM_001165963.4(SCN1A):c.379C>G(p.His127Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,548,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H127R) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 10.0

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 (HGNC:):

SCN1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-166058573-T-C is described in Lovd as [Pathogenic].

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.878

BP6

Variant 2-166058574-G-C is Benign according to our data. Variant chr2-166058574-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195131.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

BS2

High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4 linkuse as main transcript	c.379C>G	p.His127Asp	missense_variant	5/29	ENST00000674923.1	NP_001159435.1	P35498-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN1A	ENST00000674923.1 linkuse as main transcript	c.379C>G	p.His127Asp	missense_variant	5/29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 linkuse as main transcript	c.379C>G	p.His127Asp	missense_variant	4/28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 linkuse as main transcript	c.379C>G	p.His127Asp	missense_variant	2/26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.1 linkuse as main transcript	c.379C>G	p.His127Asp	missense_variant	2/26	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000678

AC:

AN:

250644

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135552

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000155

AC:

216

AN:

1396626

Hom.:

Cov.:

AF XY:

0.000156

AC XY:

109

AN XY:

698776

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000197

Gnomad4 OTH exome

AF:

0.000121

GnomAD4 genome

AF:

0.000105

AC:

AN:

151998

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000279

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SCN1A: PM5, PP3, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2024	Reported as an apparently de novo change in an individual with clinical features of borderline Dravet syndrome; however, paternity was not established. In the same paper, p.H127D was identified in another individual with classic Dravet syndrome who had another missense variant (p.P1451S) in SCN1A (PMID: 21248271); This substitution is predicted to be in the N-terminal cytoplasmic domain; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20831750, 28150151, 28202706, 29655203, 32090326, 32725632, 34598035, 35711923, 37194601, 35074891, 21248271, 38410936) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

Aug 09, 2024

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

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

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

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

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

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.88

D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

3.5

.;.;.;H;H;.;H;H;H;H

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.5

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

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.011

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

Polyphen

0.0010

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

Vest4

0.94, 0.93, 0.93

MVP

0.99

MPC

0.93

ClinPred

0.92

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.99

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