rs767045134

chr2-166041293-T-Achr2-166041293-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM5 PP2 PP3 PP5

The NM_001165963.4(SCN1A):c.2353A>T(p.Met785Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M785V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.02

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_001165963.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-166041293-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 189917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, SCN1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796
• PP5: Variant 2-166041293-T-A is Pathogenic according to our data. Variant chr2-166041293-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521545.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.2353A>T	p.Met785Leu	missense_variant	16/29	ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.2353A>T	p.Met785Leu	missense_variant	16/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.487+5163T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251260 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461752 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 785 of the SCN1A protein (p.Met785Leu). This variant is present in population databases (rs767045134, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 521545). 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 expected to disrupt SCN1A protein function with a positive predictive value of 95%. This variant disrupts the p.Met785 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21248271; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T;T;T;.;T;.;.;T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
Polyphen		0.087, 0.80	.;.;.;B;P;.;B;P;P;.
Vest4		0.76, 0.74, 0.74, 0.75
MutPred		0.42		.;Gain of catalytic residue at M785 (P = 0.1246);.;Gain of catalytic residue at M785 (P = 0.1246);.;.;Gain of catalytic residue at M785 (P = 0.1246);.;.;.;
MVP		0.99
MPC		1.6
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.85
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs767045134; hg19: chr2-166897803;