rs760676898

Positions:

• chr2-165991393-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_001165963.4(SCN1A):​c.5882T>C​(p.Ile1961Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. I1961V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.19

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 3 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 223) in uniprot entity SCN1A_HUMAN there are 69 pathogenic changes around while only 26 benign (73%) in NM_001165963.4
• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22514677).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.5882T>C	p.Ile1961Thr	missense_variant	29/29	ENST00000674923.1
LOC102724058	NR_110598.1	n.176-24220A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.5882T>C	p.Ile1961Thr	missense_variant	29/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.193-24220A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250720 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135482

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461536 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727058

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 25, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt SCN1A protein function. This variant has not been reported in the literature in individuals with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 206884). This variant is present in population databases (rs760676898, ExAC 0.006%). This sequence change replaces isoleucine with threonine at codon 1961 of the SCN1A protein (p.Ile1961Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. -

Generalized epilepsy with febrile seizures plus, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing;provider interpretation

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Feb 23, 2018

This variant was identified in an 11 year old female with autism spectrum disorder, global developmental delay, microcephaly, coordination disorder, a single seizure, imperforate anus, intermittent exotropia, and history of hydronephrosis. Initial EEG at age 3 was normal; EEG at age 4 following a single unprovoked seizure showed biposterior slowing. There is no paternal history of developmental delays or seizures. The variant is present in the gnomAD South Asian population at 0.0032%. Computational prediction models are inconsistent. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Benign	0.71
DEOGEN2	Uncertain	0.46	.;.;.;T;.;T;.;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.69	T;T;T;T;.;.;.;T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	0.13	.;.;.;N;.;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.1	.;.;.;N;.;N;.;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.11	.;.;.;T;.;T;.;T;T
Sift4G	Benign	0.60	.;.;.;T;.;T;.;T;T
Polyphen		0.018	.;.;.;.;B;.;B;B;.
Vest4		0.16, 0.15, 0.14, 0.24
MutPred		0.52		.;.;.;Loss of stability (P = 0.0012);.;Loss of stability (P = 0.0012);.;.;.;
MVP		0.17
MPC		0.91
ClinPred		0.18	T
GERP RS		5.7
Varity_R		0.17
gMVP		0.33

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: rs760676898; hg19: chr2-166847903;