2-166012276-C-G

Variant names:

• chr2-166012276-C-G
• rs750364705
• NM_001165963.4:c.3712G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_001165963.4(SCN1A):​c.3712G>C​(p.Glu1238Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,194 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1238K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90
• Publications: 1 publications found

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

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001165963.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-166012276-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 808859.
• 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 familial or sporadic hemiplegic migraine, myoclonic-astatic epilepsy, arthrogryposis, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, type 2, migraine, familial hemiplegic, 3, developmental and epileptic encephalopathy, 6A, familial hemiplegic migraine, generalized epilepsy with febrile seizures plus, genetic developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.3712G>C	p.Glu1238Gln	missense_variant	Exon 22 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.3712G>C	p.Glu1238Gln	missense_variant	Exon 22 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.3712G>C	p.Glu1238Gln	missense_variant	Exon 21 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.3679G>C	p.Glu1227Gln	missense_variant	Exon 19 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.3628G>C	p.Glu1210Gln	missense_variant	Exon 21 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246472 AF XY: 0.00000750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454194 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 723564

African (AFR) AF: 0.00 AC: 0 AN: 33206

American (AMR) AF: 0.0000451 AC: 2 AN: 44308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25930

East Asian (EAS) AF: 0.00 AC: 0 AN: 39472

South Asian (SAS) AF: 0.00 AC: 0 AN: 85932

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106366

Other (OTH) AF: 0.00 AC: 0 AN: 59980

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy Uncertain:1

Feb 07, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with glutamine at codon 1238 of the SCN1A protein (p.Glu1238Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs750364705, ExAC 0.01%) but has not been reported in the literature in individuals with a SCN1A-related disease. A different variant at this codon, c.3714A>C (p.Glu1238Asp), and two variants at the adjacent codon, c.3715G>T (p.D1239Y) and c.3716A>G (p.D1239G), have all been seen in individuals affected with epilepsy (PMID: 16713920, 17347258, 18930999), however the clinical significance of these variants is unknown. This variant is in the extracellular loop between segments 1 & 2 of the D3 domain in SCN1A, at a glutamic acid residue that is highly conserved across ion channel genes (PMID: 18804930, 22581653). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;.;.;M;.;.;M;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.9	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Pathogenic	0.0010	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0, 0.99	.;.;.;D;D;.;D;D;D;.
Vest4		0.92, 0.92, 0.93
MutPred		0.75		.;Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);.;.;Gain of helix (P = 0.062);.;.;.;
MVP		1.0
MPC		1.8
ClinPred		0.93	D
GERP RS		5.7
Varity_R		0.73
gMVP		0.97
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs750364705; hg19: chr2-166868786;