2-166046883-C-T

Variant names:

• chr2-166046883-C-T
• rs886042528
• NM_001165963.4:c.1264G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.1264G>A​(p.Val422Met) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V422E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.90
• Publications: 6 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 17 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr2-166046883-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1098587.Status of the report is no_assertion_criteria_provided, 0 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, 0.916
• PP5: Variant 2-166046883-C-T is Pathogenic according to our data. Variant chr2-166046883-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 282973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.1264G>A	p.Val422Met	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.1264G>A	p.Val422Met	missense_variant	Exon 12 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.1264G>A	p.Val422Met	missense_variant	Exon 11 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.1264G>A	p.Val422Met	missense_variant	Exon 9 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.1264G>A	p.Val422Met	missense_variant	Exon 11 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Sep 09, 2015

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This substitution is predicted to be in the cytoplasmic loop between first and second homologous domains; Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 31864146, 29056246, 22848613, 25326635, 24776920, 17347258, 23891399) -

Developmental and epileptic encephalopathy Pathogenic:1

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 422 of the SCN1A protein (p.Val422Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 22848613, 29056246). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 282973). 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%. For these reasons, this variant has been classified as Pathogenic. -

SCN1A-related disorder Pathogenic:1

Dec 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SCN1A c.1264G>A variant is predicted to result in the amino acid substitution p.Val422Met. This variant has been reported in two individuals with infantile epilepsy or Dravet syndrome (Kwong et al. 2012. PubMed ID: 22848613; Butler et al. 2017. PubMed ID: 29056246), and in Kwong et al. the variant was determined to be de novo. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant resides on the cytoplasmic side of the S6 segment in a region where disease-associated variants are common (affected residues include 418, 419, 420, 421, and 422; see, HGMD). A gene-specific machine learning-based model for clinical prediction indicates this variant is pathogenic with 93% likelihood (Heyne et al. 2020. PubMed ID 32801145). This variant is interpreted as likely pathogenic. -

Severe myoclonic epilepsy in infancy Pathogenic:1

-

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	.;.;.;M;M;.;M;M;M;M
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.0	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0, 1.0	.;.;.;D;D;.;D;D;D;.
Vest4		0.94, 0.94, 0.94, 0.93
MutPred		0.60		Gain of disorder (P = 0.1128);Gain of disorder (P = 0.1128);Gain of disorder (P = 0.1128);Gain of disorder (P = 0.1128);Gain of disorder (P = 0.1128);Gain of disorder (P = 0.1128);Gain of disorder (P = 0.1128);Gain of disorder (P = 0.1128);Gain of disorder (P = 0.1128);Gain of disorder (P = 0.1128);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.99
Mutation Taster		=0/100	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: rs886042528; hg19: chr2-166903393;