rs149715258

chr2-166043922-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1 PP2 BP4 BP6 BS2

The NM_001165963.4(SCN1A):c.1790C>A(p.Thr597Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000359 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 5.71

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_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_001165963.4
• PP2: Missense variant where missense usually causes diseases, SCN1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.39912024).
• BP6: Variant 2-166043922-G-T is Benign according to our data. Variant chr2-166043922-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206774.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
• BS2: High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.1790C>A	p.Thr597Asn	missense_variant	14/29	ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.1790C>A	p.Thr597Asn	missense_variant	14/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.487+7792G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251334 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135824

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727246

Gnomad4 AFR exome AF: 0.000627

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: 0.0000108

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74458

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000392 Hom.: 0

Bravo AF: 0.000166

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 27, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2019	The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); 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 the first and second homologous domains; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 29, 2020	- -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 597 of the SCN1A protein (p.Thr597Asn). This variant is present in population databases (rs149715258, gnomAD 0.03%). 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: 206774). 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%. 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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;T;T;T;.;T;.;.;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.70	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
Polyphen		0.26, 0.78	.;.;.;B;P;.;B;P;P;.
Vest4		0.67, 0.61, 0.63, 0.58
MVP		0.88
MPC		1.8
ClinPred		0.26	T
GERP RS		5.4
Varity_R		0.67
gMVP		0.75

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: rs149715258; hg19: chr2-166900432;