chr2-166073620-A-G

Position:

• chr2-166073620-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.2T>C​(p.Met1?) variant causes a start lost 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN1A NM_001165963.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.31

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-166073620-A-G is Pathogenic according to our data. Variant chr2-166073620-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 461262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.2T>C	p.Met1?	start_lost	4/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.2T>C	p.Met1?	start_lost	4/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.2T>C	p.Met1?	start_lost	3/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.2T>C	p.Met1?	start_lost	1/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.2T>C	p.Met1?	start_lost	1/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2023

This variant disrupts a region of the SCN1A protein in which other variant(s) (p.Arg28Cys) have been determined to be pathogenic (PMID: 18804930; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This sequence change affects the initiator methionine of the SCN1A mRNA. The next in-frame methionine is located at codon 72. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with Dravet syndrome (PMID: 18930999, 21248271). ClinVar contains an entry for this variant (Variation ID: 461262). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 01, 2017

The c.2 T>C pathogenic variant in the SCN1A gene has been reported previously in a patient with Dravet syndrome (Zuberi et al., 2011). The variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. Additionally, the c.2 T>C variant is not observed in large population cohorts (Lek et al., 2016), and parental testing indicates that this variant occurred de novo in this individual. Therefore, c.2 T>C is interpreted to be a pathogenic variant." -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	.;.;.;D;.;.;D;.;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;D;.;.;D;D;.
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.9	.;.;.;D;.;.;D;.;D;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D;.
Sift4G	Uncertain	0.0020	.;.;.;D;.;.;D;.;D;D;.
Polyphen		0.89	.;.;.;.;P;.;.;P;P;.;.
Vest4		0.92, 0.90, 0.88, 0.84
MutPred		0.92		Gain of catalytic residue at M1 (P = 0.0291);Gain of catalytic residue at M1 (P = 0.0291);Gain of catalytic residue at M1 (P = 0.0291);Gain of catalytic residue at M1 (P = 0.0291);Gain of catalytic residue at M1 (P = 0.0291);Gain of catalytic residue at M1 (P = 0.0291);Gain of catalytic residue at M1 (P = 0.0291);Gain of catalytic residue at M1 (P = 0.0291);Gain of catalytic residue at M1 (P = 0.0291);Gain of catalytic residue at M1 (P = 0.0291);Gain of catalytic residue at M1 (P = 0.0291);
MVP		0.95
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.84
gMVP		0.37

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: rs1553561023; hg19: chr2-166930130;