2-166046970-G-T

Variant names:

• chr2-166046970-G-T
• rs121917929
• NM_001165963.4:c.1177C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_001165963.4(SCN1A):​c.1177C>A​(p.Arg393Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R393H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 5.57

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)

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-166046969-C-T is described in Lovd as [Pathogenic].
• 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 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, 0.929
• PP5: Variant 2-166046970-G-T is Pathogenic according to our data. Variant chr2-166046970-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 68504.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.1177C>A	p.Arg393Ser	missense_variant	Exon 12 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.1177C>A	p.Arg393Ser	missense_variant	Exon 12 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.1177C>A	p.Arg393Ser	missense_variant	Exon 11 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.1177C>A	p.Arg393Ser	missense_variant	Exon 9 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.1177C>A	p.Arg393Ser	missense_variant	Exon 9 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Apr 25, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg393 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17054684, 22848613, 18930999, 21868258). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 and their clinical significance is uncertain. This variant has been observed to be de novo in an individual affected with severe myoclonic epilepsy in infancy (PMID: 17054684). ClinVar contains an entry for this variant (Variation ID: 68504). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with serine at codon 393 of the SCN1A protein (p.Arg393Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. -

Severe myoclonic epilepsy in infancy Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;.;.;M;M;.;M;M;M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.9	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Benign	0.065	.;.;.;T;.;.;T;.;T;T
Polyphen		1.0, 0.89	.;.;.;D;P;.;D;P;P;.
Vest4		0.95, 0.98, 0.98, 0.95
MutPred		0.70		Gain of methylation at K397 (P = 0.0498);Gain of methylation at K397 (P = 0.0498);Gain of methylation at K397 (P = 0.0498);Gain of methylation at K397 (P = 0.0498);Gain of methylation at K397 (P = 0.0498);Gain of methylation at K397 (P = 0.0498);Gain of methylation at K397 (P = 0.0498);Gain of methylation at K397 (P = 0.0498);Gain of methylation at K397 (P = 0.0498);Gain of methylation at K397 (P = 0.0498);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.89
gMVP		1.0

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: rs121917929; hg19: chr2-166903480;