rs121917912

Positions:

chr2-166012254-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PP2PP3_ModeratePP5_Very_Strong

The NM_001165963.4(SCN1A):c.3734G>A(p.Arg1245Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000435 in 1,609,000 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 6.12

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 Pathogenic. Variant got 13 ACMG points.

PM1

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

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, 0.886

PP5

Variant 2-166012254-C-T is Pathogenic according to our data. Variant chr2-166012254-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4 linkuse as main transcript	c.3734G>A	p.Arg1245Gln	missense_variant	22/29	ENST00000674923.1	NP_001159435.1
LOC102724058	NR_110598.1 linkuse as main transcript	n.176-3359C>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.3734G>A	p.Arg1245Gln	missense_variant	22/29		NM_001165963.4	ENSP00000501589	P4	P35498-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.193-3359C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1457874

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725290

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000451

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151126

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73814

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000148

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Generalized epilepsy with febrile seizures plus, type 2

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jan 29, 2021	The inherited c.3734G>A (p.Arg1245Gln) variant identified in the SCN1A gene substitutes a very well conserved Arginine for Glutamine at amino acid 1245/2010(exon 22/29). This variant is found with low frequency in gnomAD(v3.0) (1 heterozygote, 0 homozygotes; allele frequency: 6.62e-6) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.001) and Pathogenic (REVEL; score: 0.808) to the function of the canonical transcript. This variant is reported as Pathogenic / Likely Pathogenic in ClinVar (VarID: 68533). The c.3734G>A (p.Arg1245Gln) variant identified here has been previously reported in several individuals in the literature with SCN1A associated epilepsy syndromes [PMID:17054684; PMID: 21906962; PMID: 28202706]. Given its low frequency in population databases, observation in several affected individuals in the literature, and in silico predictions of pathogenicity, the inherited c.3734G>A (p.Arg1245Gln) variant identified in the SCN1A gene is reported as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 19, 2022	- -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1245 of the SCN1A protein (p.Arg1245Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe myoclonic epilepsy of infancy (PMID: 17054684, 21906962, 28202706). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68533). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 02, 2024

Identified in multiple patients with Dravet syndrome or other SCN1A-related epilepsy referred for genetic testing at GeneDx and in published literature (PMID: 28202706, 21906962, 36993157); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the extracellular loop between the S1 and S2 transmembrane segments of the third homologous domain; This variant is associated with the following publications: (PMID: 18804930, 21906962, 17054684, 24331359, 32347949, 24136861, 17381446, 31440721, 36993157, 35074891, 28202706) -

Severe myoclonic epilepsy in infancy

Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

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

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.89

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.5

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

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.024

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

Polyphen

1.0, 1.0

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

Vest4

0.84, 0.89, 0.87, 0.85

MutPred

0.40

.;Gain of ubiquitination at K1246 (P = 0.1278);.;Gain of ubiquitination at K1246 (P = 0.1278);.;.;Gain of ubiquitination at K1246 (P = 0.1278);.;.;.;

MVP

1.0

MPC

1.1

ClinPred

0.99

GERP RS

5.7

Varity_R

0.61

gMVP

0.88

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