2-166012274-T-G

Variant names:

• chr2-166012274-T-G
• rs121917973
• NM_001165963.4:c.3714A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 7P and 5B. PM1 PM5 PP2 PP3_Moderate BP6 BS2

The NM_001165963.4(SCN1A):​c.3714A>C​(p.Glu1238Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,606,018 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. E1238K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2 O:1
• Conservation: PhyloP100: 1.40
• Publications: 9 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001165963.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-166012276-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 808859.
• PP2: Missense variant in the SCN1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 848 curated pathogenic missense variants (we use a threshold of 10). The gene has 89 curated benign missense variants. Gene score misZ: 5.2206 (above the threshold of 3.09). Trascript score misZ: 7.6022 (above the threshold of 3.09). GenCC associations: The gene is linked to familial or sporadic hemiplegic migraine, myoclonic-astatic epilepsy, arthrogryposis, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, type 2, migraine, familial hemiplegic, 3, developmental and epileptic encephalopathy, 6A, familial hemiplegic migraine, generalized epilepsy with febrile seizures plus, genetic developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841
• BP6: Variant 2-166012274-T-G is Benign according to our data. Variant chr2-166012274-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 68532.
• BS2: High AC in GnomAd4 at 13 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165963.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	NM_001165963.4	MANE Select	c.3714A>C	p.Glu1238Asp	missense	Exon 22 of 29	NP_001159435.1
	SCN1A	NM_001202435.3		c.3714A>C	p.Glu1238Asp	missense	Exon 21 of 28	NP_001189364.1
	SCN1A	NM_001353948.2		c.3714A>C	p.Glu1238Asp	missense	Exon 20 of 27	NP_001340877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.3714A>C	p.Glu1238Asp	missense	Exon 22 of 29	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.3714A>C	p.Glu1238Asp	missense	Exon 21 of 28	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.3681A>C	p.Glu1227Asp	missense	Exon 19 of 26	ENSP00000364554.3

Frequencies

GnomAD3 genomes AF: 0.0000859 AC: 13 AN: 151308 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000529

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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000486 AC: 12 AN: 246788 AF XY: 0.0000374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000881

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000451

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1454592 Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 10 AN XY: 723772

African (AFR) AF: 0.0000301 AC: 1 AN: 33200

American (AMR) AF: 0.0000902 AC: 4 AN: 44332

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25928

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.00 AC: 0 AN: 85952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000904 AC: 10 AN: 1106690

Other (OTH) AF: 0.0000667 AC: 4 AN: 59994

GnomAD4 genome AF: 0.0000859 AC: 13 AN: 151426 Hom.: 0 Cov.: 32 AF XY: 0.0000946 AC XY: 7 AN XY: 74030

African (AFR) AF: 0.0000724 AC: 3 AN: 41462

American (AMR) AF: 0.000528 AC: 8 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67474

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000189

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Apr 14, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 24, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported multiple times in patients with epilepsy in published literature; however, parental testing was not reported, and one individual was also found to have a second SCN1A variant (Harkin et al., 2007; Zuberi et al., 2011; Kodera et al., 2013; SCN1A Variant Database); This substitution is predicted to be within the extracellular loop between the S1 and S2 transmembrane segments of the third homologous domain; Observed in heterozygous state in many unrelated healthy adult individuals tested at GeneDx; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 16713913, 17166794, 23884151, 19586930, 21248271, 28150151, 16713920, 23662938, 19585586, 24136861, 18804930, 32090326, 32180723, 31054490, 17347258, 35074891)

Severe myoclonic epilepsy in infancy Uncertain:1 Other:1

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2 Uncertain:1

Sep 17, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The inherited c.3714A>C (p.Glu1238Asp) variant identified in the SCN1A gene substitutes a very well conserved Glutamic Acid for AsparticAcid at amino acid 1238/1999 (exon 22/29). SCN1A is an alternatively spliced transcript and this variant is also called c.3681A>C (p.Glu1227Asp) when annotated from transcript NM_006920.6. This variant is found with low frequency in gnomAD(v3.1.1) (13 heterozygotes, 0 homozygotes; allele frequency:8.6e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.00) and Pathogenic (REVEL; score:0.9269) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:68532), and has beenidentified in several affected individuals in the literature, [PMID:31054490; PMID:23662938; PMID:17347258]. The p.Glu1238 reside is within the extracellular loop between the S1and S2 domains of the 3rd homologous domain. The inherited c.3714A>C (p.Glu1238Asp) variant identified in the SCN1A gene is reported as a Variant of Uncertian Significance.

Inborn genetic diseases Benign:1

Apr 04, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Developmental and epileptic encephalopathy Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.66		Gain of relative solvent accessibility (P = 0.09)
MVP		1.0
MPC		1.6
ClinPred		0.80	D
GERP RS		3.3
Varity_R		0.71
gMVP		0.96
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs121917973; hg19: chr2-166868784;