chr2-166045167-T-C

Variant names:

• chr2-166045167-T-C
• rs1553545586
• NM_001165963.4:c.1538A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001165963.4(SCN1A):​c.1538A>G​(p.Glu513Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.95

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.1538A>G	p.Glu513Gly	missense_variant	Exon 13 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.1538A>G	p.Glu513Gly	missense_variant	Exon 13 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.1538A>G	p.Glu513Gly	missense_variant	Exon 12 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.1538A>G	p.Glu513Gly	missense_variant	Exon 10 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.1538A>G	p.Glu513Gly	missense_variant	Exon 10 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Jul 03, 2019

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 glycine at codon 513 of the SCN1A protein (p.Glu513Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN1A-related disease. This variant identified in the SCN1A gene is located in the cytoplasmic  interdomain linker DI/DII region of the resulting protein (PMID: 25348405, 18804930) but it is unclear how this variant impacts the function of this protein.. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;.;.;D;.;.;D;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.67	T;T;T;T;.;T;.;.;T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.9	.;.;.;L;L;.;L;L;L;L
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.7	.;.;.;D;.;.;D;.;D;D
REVEL	Uncertain	0.59
Sift	Benign	0.034	.;.;.;D;.;.;D;.;D;D
Sift4G	Benign	0.14	.;.;.;T;.;.;T;.;T;T
Polyphen		0.77, 0.73	.;.;.;P;P;.;P;P;P;.
Vest4		0.34, 0.34, 0.35, 0.35
MutPred		0.24		.;Gain of MoRF binding (P = 0.0534);Gain of MoRF binding (P = 0.0534);Gain of MoRF binding (P = 0.0534);Gain of MoRF binding (P = 0.0534);Gain of MoRF binding (P = 0.0534);Gain of MoRF binding (P = 0.0534);Gain of MoRF binding (P = 0.0534);Gain of MoRF binding (P = 0.0534);Gain of MoRF binding (P = 0.0534);
MVP		0.75
MPC		0.81
ClinPred		0.98	D
GERP RS		6.2
Varity_R		0.52
gMVP		0.63

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: rs1553545586; hg19: chr2-166901677;