rs967989950

chr2-166043893-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_001165963.4(SCN1A):c.1819T>A(p.Ser607Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,882 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S607S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.32

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 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 10 uncertain in NM_001165963.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.1819T>A	p.Ser607Thr	missense_variant	14/29	ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.1819T>A	p.Ser607Thr	missense_variant	14/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.487+7763A>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.1819T>A (p.S607T) alteration is located in exon 11 (coding exon 11) of the SCN1A gene. This alteration results from a T to A substitution at nucleotide position 1819, causing the serine (S) at amino acid position 607 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 18, 2018

This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN1A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant identified in the SCN1A gene is located in the cytoplasmic interdomain linker D1-D2 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces serine with threonine at codon 607 of the SCN1A protein (p.Ser607Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 21, 2021

Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); This substitution is predicted to be in the cytoplasmic loop between the first and second homologous domains of the protein.; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
Polyphen		0.99, 1.0	.;.;.;D;D;.;D;D;D;.
Vest4		0.71, 0.65, 0.60, 0.64
MutPred		0.26		.;Loss of MoRF binding (P = 0.1342);Loss of MoRF binding (P = 0.1342);Loss of MoRF binding (P = 0.1342);Loss of MoRF binding (P = 0.1342);Loss of MoRF binding (P = 0.1342);Loss of MoRF binding (P = 0.1342);Loss of MoRF binding (P = 0.1342);Loss of MoRF binding (P = 0.1342);Loss of MoRF binding (P = 0.1342);
MVP		0.99
MPC		1.6
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.68
gMVP		0.81

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: rs967989950; hg19: chr2-166900403;