chr2-166002660-C-T

Position:

chr2-166002660-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PM1PM5PP2PP3_ModerateBS2

The NM_001165963.4(SCN1A):c.4096G>A(p.Val1366Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000695 in 1,611,840 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. V1366L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3O:2

Conservation

PhyloP100: 7.90

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 Uncertain_significance. Variant got 3 ACMG points.

PM1

In a helix (size 24) in uniprot entity SCN1A_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_001165963.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-166002660-C-A is described in Lovd as [Likely_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, 0.879

BS2

High AC in GnomAdExome4 at 108 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4 linkuse as main transcript	c.4096G>A	p.Val1366Ile	missense_variant	24/29	ENST00000674923.1	NP_001159435.1
LOC102724058	NR_110598.1 linkuse as main transcript	n.176-12953C>T		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.4096G>A	p.Val1366Ile	missense_variant	24/29		NM_001165963.4	ENSP00000501589	P4	P35498-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.193-12953C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151644

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250240

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135252

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.0000998

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000740

AC:

108

AN:

1460078

Hom.:

Cov.:

AF XY:

0.0000785

AC XY:

AN XY:

726334

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000909

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151762

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74162

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000205

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Severe myoclonic epilepsy in infancy

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
not provided, no classification provided	literature only	Channelopathy-Associated Epilepsy Research Center	-	- -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1366 of the SCN1A protein (p.Val1366Ile). This variant is present in population databases (rs121918805, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant SCN1A-related conditions (PMID: 17507202). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68628). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN1A function (PMID: 25576396). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2024

The c.4096G>A (p.V1366I) alteration is located in exon 21 (coding exon 21) of the SCN1A gene. This alteration results from a G to A substitution at nucleotide position 4096, causing the valine (V) at amino acid position 1366 to be replaced by an isoleucine (I). In an assay testing SCN1A function, this variant showed a functionally abnormal result (Bechi 2015). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2024

In vitro functional studies indicate reduced cell surface expression, leading to a loss-of-function effect; however the effect was not as strong as other pathogenic variants (PMID: 25576396); Available evidence suggests this variant may predispose to seizures but is associated with incomplete penetrance; This substitution is predicted to be within the transmembrane segment S5 of the third homologous domain; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19586930, 23884151, 24502503, 28150151, 28664031, 32146541, 31782251, 33375447, 17507202, Shin2022, 25576396, 29655203) -

Generalized epilepsy with febrile seizures plus, type 1

Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

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

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.80

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

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.88

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.95

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

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.014

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

Polyphen

1.0, 0.92

.;.;D;P;.;D;P;P;.

Vest4

0.70, 0.76, 0.75, 0.75

MVP

0.99

MPC

1.6

ClinPred

0.97

GERP RS

5.5

Varity_R

0.50

gMVP

0.94

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