rs121917973

Positions:

• chr2-166012274-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PP2 PP3_Moderate BS2

The NM_001165963.4(SCN1A):​c.3714A>C​(p.Glu1238Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,606,018 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).

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1 O:1
• Conservation: PhyloP100: 1.40

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-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

LOC102724058 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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, 0.841
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.3714A>C	p.Glu1238Asp	missense_variant	22/29	ENST00000674923.1	NP_001159435.1
LOC102724058	NR_110598.1	n.176-3339T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.3714A>C	p.Glu1238Asp	missense_variant	22/29		NM_001165963.4	ENSP00000501589	P4
SCN1A-AS1	ENST00000651574.1	n.193-3339T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000859 AC: 13 AN: 151308 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000529

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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000486 AC: 12 AN: 246788 Hom.: 0 AF XY: 0.0000374 AC XY: 5 AN XY: 133558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000881

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000451

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1454592 Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 10 AN XY: 723772

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000902

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000904

Gnomad4 OTH exome AF: 0.0000667

GnomAD4 genome AF: 0.0000859 AC: 13 AN: 151426 Hom.: 0 Cov.: 32 AF XY: 0.0000946 AC XY: 7 AN XY: 74030

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000528

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000296

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000669 Hom.: 0

Bravo AF: 0.000189

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2023	Reported multiple times in patients with epilepsy in published literature; however, parental testing was not reported, and one individual was also found to have a second SCN1A variant (Harkin et al., 2007; Zuberi et al., 2011; Kodera et al., 2013; SCN1A Variant Database); This substitution is predicted to be within the extracellular loop between the S1 and S2 transmembrane segments of the third homologous domain; Observed in heterozygous state in many unrelated healthy adult individuals tested at GeneDx; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 16713913, 17166794, 23884151, 19586930, 21248271, 28150151, 16713920, 23662938, 19585586, 24136861, 18804930, 32090326, 32180723, 31054490, 17347258, 35074891) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -

Severe myoclonic epilepsy in infancy Uncertain:1 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Sep 17, 2021

The inherited c.3714A>C (p.Glu1238Asp) variant identified in the SCN1A gene substitutes a very well conserved Glutamic Acid for AsparticAcid at amino acid 1238/1999 (exon 22/29). SCN1A is an alternatively spliced transcript and this variant is also called c.3681A>C (p.Glu1227Asp) when annotated from transcript NM_006920.6. This variant is found with low frequency in gnomAD(v3.1.1) (13 heterozygotes, 0 homozygotes; allele frequency:8.6e-5) 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:0.00) and Pathogenic (REVEL; score:0.9269) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:68532), and has beenidentified in several affected individuals in the literature, [PMID:31054490; PMID:23662938; PMID:17347258]. The p.Glu1238 reside is within the extracellular loop between the S1and S2 domains of the 3rd homologous domain. The inherited c.3714A>C (p.Glu1238Asp) variant identified in the SCN1A gene is reported as a Variant of Uncertian Significance. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;D;.;.;D;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	.;.;.;M;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.9	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.036	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0, 0.98	.;.;.;D;D;.;D;D;D;.
Vest4		0.89, 0.88, 0.91, 0.90
MutPred		0.66		.;Gain of relative solvent accessibility (P = 0.09);.;Gain of relative solvent accessibility (P = 0.09);.;.;Gain of relative solvent accessibility (P = 0.09);.;.;.;
MVP		1.0
MPC		1.6
ClinPred		0.80	D
GERP RS		3.3
Varity_R		0.71
gMVP		0.96

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

Other links and lift over

dbSNP: rs121917973; hg19: chr2-166868784;