rs121917965

Variant names:

• chr2-166058652-G-A
• rs121917965
• NM_001165963.4:c.301C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166058652-G-A
• chr2-166058652-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001353961.2(SCN1A):​c.-2125C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001353961.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.93

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 2-166058652-G-A is Pathogenic according to our data. Variant chr2-166058652-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166058652-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.301C>T	p.Arg101Trp	missense_variant	Exon 5 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.301C>T	p.Arg101Trp	missense_variant	Exon 5 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.301C>T	p.Arg101Trp	missense_variant	Exon 4 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.301C>T	p.Arg101Trp	missense_variant	Exon 2 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.301C>T	p.Arg101Trp	missense_variant	Exon 2 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:3 Other:1

Dec 20, 2014

Center for Bioinformatics, Peking University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Lifecell International Pvt. Ltd

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variant (c.301C>T) in exon 5 of the SCN1A gene that results in the amino acid substitution from Arginine to Tryptophan at codon 101 (p.Arg101Trp) was identified. There is a moderate physicochemical difference between Arginine and Tryptophan. The observed variant is not present in both the 1000 Genomes and gnomAD databases. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. The Missense Variants Z-Score for this variant is 5.61. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. (DOI: 10.1038/nature19057). This variant has previously been reported for Dravet syndrome by Usluer S et al., 2016. This variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 68527 as of 2020-06-04). Based on the above evidence this variant has been classified as Likely pathogenic according to the ACMG guidelines. -

Aug 30, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM5_STR,PS2_MOD,PS4_MOD,PM2_SUP,PP2,PP3 -

not provided Pathogenic:3

Jan 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This substitution is predicted to be within the N-terminal cytoplasmic domain; Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19585586, 20431604, 26096185, 27113213, 27236449, 29933521, 17347258, 18930999, 29852413, 30619928, 31164858, 31864146, 32090326, 29573403, 33278787, 31031587) -

Aug 31, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Migraine, familial hemiplegic, 3 Pathogenic:1

May 06, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP2,PP3,PM2,PM1. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 101 of the SCN1A protein (p.Arg101Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe myoclonic epilepsyof infancy (SMEI) and Dravet Syndrome (PMID: 17347258, 20431604, 24168886, 27113213, 27236449). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68527). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg101 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20431604, 23195492, 23808377, 24328833, 25885068). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	.;.;.;H;H;.;H;H;H;H
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.1	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0	.;.;.;.;D;.;.;D;D;.
Vest4		0.94, 0.95, 0.95, 0.96
MutPred		0.72		Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs121917965; hg19: chr2-166915162;