chr2-166047721-T-C

Variant names:

• chr2-166047721-T-C
• rs794726713
• NM_001165963.4:c.1076A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_001165963.4(SCN1A):​c.1076A>G​(p.Asn359Ser) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N359K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 8.02
• Publications: 5 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)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr2-166047720-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 801814.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.873
• PP5: Variant 2-166047721-T-C is Pathogenic according to our data. Variant chr2-166047721-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 189864.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.1076A>G	p.Asn359Ser	missense_variant	Exon 11 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.1076A>G	p.Asn359Ser	missense_variant	Exon 11 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.1076A>G	p.Asn359Ser	missense_variant	Exon 10 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.1076A>G	p.Asn359Ser	missense_variant	Exon 8 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.1076A>G	p.Asn359Ser	missense_variant	Exon 10 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:2

Jul 10, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS2,PS4_MOD,PM1,PM2_SUP,PM5,PP3 -

Dec 20, 2014

Center for Bioinformatics, Peking University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:1 Uncertain:1

Sep 06, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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; This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the first homologous domain; This variant is associated with the following publications: (PMID: 24168886, 21248271, 34816733, 29056246, 29655203, 32090326, 35074891) -

Apr 01, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Aug 26, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1076A>G (p.N359S) alteration is located in exon 8 (coding exon 8) of the SCN1A gene. This alteration results from an A to G substitution at nucleotide position 1076, causing the asparagine (N) at amino acid position 359 to be replaced by a serine (S). for SCN1A-related seizure disorders; however, its clinical significance for SCN1A-related hemiplegic migraine is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in multiple individuals with features consistent with SCN1A-related seizure disorders, including multiple cases of reported de novo occurrence (Zuberi, 2011; Gaily, 2013; Butler, 2017; Chahal, 2021; Brunklaus, 2022; Veltra, 2024). This amino acid position is well conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Developmental and epileptic encephalopathy Pathogenic:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 359 of the SCN1A protein (p.Asn359Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 21248271). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 189864). 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%. This variant disrupts the p.Asn359 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 23708187, 23808377, 29142202), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	.;.;.;M;M;.;M;M;M;M
PhyloP100		8.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.9	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	.;.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.019	.;.;.;D;.;.;D;.;D;D
Polyphen		0.98, 0.99	.;.;.;D;D;.;D;D;D;.
Vest4		0.72, 0.71, 0.71, 0.77
MutPred		0.48		Loss of solvent accessibility (P = 0.0352);Loss of solvent accessibility (P = 0.0352);Loss of solvent accessibility (P = 0.0352);Loss of solvent accessibility (P = 0.0352);Loss of solvent accessibility (P = 0.0352);Loss of solvent accessibility (P = 0.0352);Loss of solvent accessibility (P = 0.0352);Loss of solvent accessibility (P = 0.0352);Loss of solvent accessibility (P = 0.0352);Loss of solvent accessibility (P = 0.0352);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.58
gMVP		0.99
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs794726713; hg19: chr2-166904231;