2-166045080-C-T

Variant names:

• chr2-166045080-C-T
• rs121918817
• NM_001165963.4:c.1625G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001165963.4(SCN1A):​c.1625G>A​(p.Arg542Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,614,152 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (5 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:13 O:1
• Conservation: PhyloP100: 2.41

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 Benign. Variant got -12 ACMG points.

• 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 migraine, familial hemiplegic, 3, familial hemiplegic migraine, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, myoclonic-astatic epilepsy, developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 6, familial or sporadic hemiplegic migraine, arthrogryposis, Lennox-Gastaut syndrome, generalized epilepsy with febrile seizures plus, type 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009377807).
• BP6: Variant 2-166045080-C-T is Benign according to our data. Variant chr2-166045080-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68588.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=4, Uncertain_significance=1, Pathogenic=1, not_provided=1}. Variant chr2-166045080-C-T is described in Lovd as [Benign]. Variant chr2-166045080-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00153 (233/152298) while in subpopulation NFE AF= 0.002 (136/68022). AF 95% confidence interval is 0.00173. There are 2 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 233 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.1625G>A	p.Arg542Gln	missense_variant	Exon 13 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.1625G>A	p.Arg542Gln	missense_variant	Exon 13 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.1625G>A	p.Arg542Gln	missense_variant	Exon 12 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.1625G>A	p.Arg542Gln	missense_variant	Exon 10 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.1625G>A	p.Arg542Gln	missense_variant	Exon 10 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152180 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00170 AC: 427 AN: 251248 Hom.: 0 AF XY: 0.00163 AC XY: 222 AN XY: 135826

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00152 AC: 2216 AN: 1461854 Hom.: 5 Cov.: 32 AF XY: 0.00147 AC XY: 1071 AN XY: 727234

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.00129

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152298 Hom.: 2 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74466

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00200

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00252 Hom.: 0

Bravo AF: 0.00158

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00153 AC: 186

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:13 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

Nov 09, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN1A c.1625G>A (p.Arg542Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251248 control chromosomes. The observed variant frequency is approximately 95 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN1A causing SCN1A-Related Seizure Disorder phenotype (1.8e-05), strongly suggesting that the variant is benign. Although reported in the literature, to our knowledge, no occurrence of c.1625G>A in individuals affected with SCN1A-Related Seizure Disorder and no conclusive experimental evidence demonstrating its impact on protein function have been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments but a predominant consensus as benign/likely benign (n=7). Based on the evidence outlined above, the variant was classified as likely benign. -

Jun 06, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2018

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN1A: BS1 -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Self-limited epilepsy with centrotemporal spikes Pathogenic:1

Jan 01, 2017

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Significance: Pathogenic

Review Status: flagged submission

Collection Method: case-control

CAADphred>15 -

Autism Uncertain:1

-

UniProtKB/Swiss-Prot

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Severe myoclonic epilepsy in infancy Uncertain:1

Oct 04, 2019

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, BS2 -

Inborn genetic diseases Benign:1

Apr 03, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3;C5543353:Developmental and epileptic encephalopathy 6B Benign:1

Sep 24, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

SCN1A-related disorder Benign:1

Apr 24, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Intellectual disability Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Epilepsy;C0751122:Severe myoclonic epilepsy in infancy Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	.;.;.;D;.;.;D;.;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D;D;D;.;D;.;.;D;D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.0094	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.9	.;.;.;M;M;.;M;M;M;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.9	.;.;.;D;.;.;D;.;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.048	.;.;.;D;.;.;D;.;D;D
Sift4G	Benign	0.15	.;.;.;T;.;.;T;.;T;T
Polyphen		0.42, 0.040	.;.;.;B;B;.;B;B;B;.
Vest4		0.23, 0.24, 0.25, 0.25
MVP		0.92
MPC		1.1
ClinPred		0.041	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.62

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: rs121918817; hg19: chr2-166901590; COSMIC: COSV57664204;