rs144679294

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001165963.4(SCN1A):ā€‹c.2889T>Cā€‹(p.Ala963=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,614,186 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0033 ( 6 hom., cov: 32)
Exomes š‘“: 0.0041 ( 21 hom. )

Consequence

SCN1A
NM_001165963.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.597
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 -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BP6
Variant 2-166037833-A-G is Benign according to our data. Variant chr2-166037833-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 93642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166037833-A-G is described in Lovd as [Likely_benign]. Variant chr2-166037833-A-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.597 with no splicing effect.
BS2
High AC in GnomAd4 at 500 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN1ANM_001165963.4 linkuse as main transcriptc.2889T>C p.Ala963= synonymous_variant 18/29 ENST00000674923.1 NP_001159435.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN1AENST00000674923.1 linkuse as main transcriptc.2889T>C p.Ala963= synonymous_variant 18/29 NM_001165963.4 ENSP00000501589 P4P35498-1
SCN1A-AS1ENST00000651574.1 linkuse as main transcriptn.487+1703A>G intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.00329
AC:
500
AN:
152178
Hom.:
6
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000700
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00484
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00373
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00535
Gnomad OTH
AF:
0.00382
GnomAD3 exomes
AF:
0.00306
AC:
769
AN:
251486
Hom.:
1
AF XY:
0.00320
AC XY:
435
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.000861
Gnomad AMR exome
AF:
0.00292
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00317
Gnomad FIN exome
AF:
0.000277
Gnomad NFE exome
AF:
0.00461
Gnomad OTH exome
AF:
0.00423
GnomAD4 exome
AF:
0.00415
AC:
6065
AN:
1461890
Hom.:
21
Cov.:
32
AF XY:
0.00415
AC XY:
3021
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00125
Gnomad4 AMR exome
AF:
0.00329
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00376
Gnomad4 FIN exome
AF:
0.000431
Gnomad4 NFE exome
AF:
0.00471
Gnomad4 OTH exome
AF:
0.00397
GnomAD4 genome
AF:
0.00328
AC:
500
AN:
152296
Hom.:
6
Cov.:
32
AF XY:
0.00320
AC XY:
238
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.000698
Gnomad4 AMR
AF:
0.00484
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00373
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.00535
Gnomad4 OTH
AF:
0.00378
Alfa
AF:
0.00395
Hom.:
1
Bravo
AF:
0.00329
EpiCase
AF:
0.00605
EpiControl
AF:
0.00688

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:7
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2024SCN1A: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 10, 2015- -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 09, 2012- -
Migraine, familial hemiplegic, 3 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 03, 2016This 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
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Generalized epilepsy with febrile seizures plus, type 2 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
SCN1A-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 09, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Epilepsy Benign:1
Likely 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
-0.48
CADD
Benign
1.2
DANN
Benign
0.68

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

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

Other links and lift over

dbSNP: rs144679294; hg19: chr2-166894343; API