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rs6432860

chr2-166041354-A-Gchr2-166041354-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001165963.4(SCN1A):c.2292T>C(p.Val764=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 1,613,016 control chromosomes in the GnomAD database, including 404,607 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V764V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.74 ( 41728 hom., cov: 30)
Exomes 𝑓: 0.70 ( 362879 hom. )

Consequence

SCN1A
NM_001165963.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.608
Variant links:
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)

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.74).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-166041354-A-G is Benign according to our data. Variant chr2-166041354-A-G is described in ClinVar as [Benign]. Clinvar id is 36752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166041354-A-G is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.608 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.87 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN1ANM_001165963.4 linkuse as main transcriptc.2292T>C p.Val764= synonymous_variant 16/29 ENST00000674923.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN1AENST00000674923.1 linkuse as main transcriptc.2292T>C p.Val764= synonymous_variant 16/29 NM_001165963.4 P4P35498-1
SCN1A-AS1ENST00000651574.1 linkuse as main transcriptn.487+5224A>G intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.737
AC:
111953
AN:
151804
Hom.:
41683
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.824
Gnomad AMI
AF:
0.645
Gnomad AMR
AF:
0.742
Gnomad ASJ
AF:
0.602
Gnomad EAS
AF:
0.891
Gnomad SAS
AF:
0.709
Gnomad FIN
AF:
0.755
Gnomad MID
AF:
0.525
Gnomad NFE
AF:
0.683
Gnomad OTH
AF:
0.679
GnomAD3 exomes
AF:
0.726
AC:
182465
AN:
251300
Hom.:
67219
AF XY:
0.715
AC XY:
97165
AN XY:
135820
show subpopulations
Gnomad AFR exome
AF:
0.830
Gnomad AMR exome
AF:
0.809
Gnomad ASJ exome
AF:
0.599
Gnomad EAS exome
AF:
0.896
Gnomad SAS exome
AF:
0.686
Gnomad FIN exome
AF:
0.745
Gnomad NFE exome
AF:
0.679
Gnomad OTH exome
AF:
0.677
GnomAD4 exome
AF:
0.703
AC:
1026435
AN:
1461094
Hom.:
362879
Cov.:
42
AF XY:
0.699
AC XY:
508089
AN XY:
726928
show subpopulations
Gnomad4 AFR exome
AF:
0.827
Gnomad4 AMR exome
AF:
0.803
Gnomad4 ASJ exome
AF:
0.601
Gnomad4 EAS exome
AF:
0.895
Gnomad4 SAS exome
AF:
0.683
Gnomad4 FIN exome
AF:
0.748
Gnomad4 NFE exome
AF:
0.691
Gnomad4 OTH exome
AF:
0.696
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.738
AC:
112059
AN:
151922
Hom.:
41728
Cov.:
30
AF XY:
0.741
AC XY:
55013
AN XY:
74254
show subpopulations
Gnomad4 AFR
AF:
0.823
Gnomad4 AMR
AF:
0.743
Gnomad4 ASJ
AF:
0.602
Gnomad4 EAS
AF:
0.891
Gnomad4 SAS
AF:
0.709
Gnomad4 FIN
AF:
0.755
Gnomad4 NFE
AF:
0.682
Gnomad4 OTH
AF:
0.682
Alfa
AF:
0.696
Hom.:
22862
Bravo
AF:
0.741
Asia WGS
AF:
0.790
AC:
2745
AN:
3476
EpiCase
AF:
0.674
EpiControl
AF:
0.656

ClinVar

Significance: Benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 12, 2016- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMay 11, 2020- -
Migraine, familial hemiplegic, 3 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 31, 2015This 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
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Generalized epilepsy with febrile seizures plus Benign:1
Benign, no assertion criteria providedclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 21, 2011- -
Generalized epilepsy with febrile seizures plus, type 2 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Epilepsy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.74
Cadd
Benign
0.43
Dann
Benign
0.61
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs6432860; hg19: chr2-166897864; COSMIC: COSV57690570; COSMIC: COSV57690570; API