rs121917910

Positions:

• chr2-166009797-T-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BP6 BS2

The NM_001165963.4(SCN1A):​c.3924A>T​(p.Glu1308Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000852 in 1,607,484 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1308K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:11 O:1
• Conservation: PhyloP100: 1.27

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)

LOC102724058 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_001165963.4
• PP2: Missense variant where missense usually causes diseases, SCN1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.057480246).
• BP6: Variant 2-166009797-T-A is Benign according to our data. Variant chr2-166009797-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68534.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, not_provided=1, Likely_benign=6, Benign=2}. Variant chr2-166009797-T-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 97 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.3924A>T	p.Glu1308Asp	missense_variant	23/29	ENST00000674923.1
LOC102724058	NR_110598.1	n.176-5816T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.3924A>T	p.Glu1308Asp	missense_variant	23/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.193-5816T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000642 AC: 97 AN: 150976 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000265

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.000483

GnomAD3 exomes AF: 0.000607 AC: 152 AN: 250236 Hom.: 0 AF XY: 0.000673 AC XY: 91 AN XY: 135242

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000509

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000873 AC: 1272 AN: 1456390 Hom.: 0 Cov.: 30 AF XY: 0.000867 AC XY: 628 AN XY: 724606

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.000180

Gnomad4 ASJ exome AF: 0.000116

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000787

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.000766

GnomAD4 genome AF: 0.000642 AC: 97 AN: 151094 Hom.: 0 Cov.: 32 AF XY: 0.000528 AC XY: 39 AN XY: 73854

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000265

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000952 Hom.: 0

Bravo AF: 0.000536

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000750 AC: 91

EpiCase AF: 0.000820

EpiControl AF: 0.00125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:11 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SCN1A: PP2, PP3, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2019	This variant is associated with the following publications: (PMID: 20729507, 18930999, 19522081, 28717674, 27881154, 26990884, 31765958, 32090326) -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 03, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2022	- -

Severe myoclonic epilepsy in infancy Benign:1 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

Migraine, familial hemiplegic, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Generalized epilepsy with febrile seizures plus, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2018

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. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

SCN1A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	-0.13
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D;D;D;D;.;D;.;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.057	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.70	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
Polyphen		0.047, 0.96	.;.;.;B;D;.;B;D;D;.
Vest4		0.44, 0.43, 0.46, 0.40
MutPred		0.47		.;Loss of loop (P = 0.0804);.;Loss of loop (P = 0.0804);.;.;Loss of loop (P = 0.0804);.;.;.;
MVP		0.95
MPC		0.71
ClinPred		0.060	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.88

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: rs121917910; hg19: chr2-166866307;