chr2-166048865-A-G

Position:

chr2-166048865-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001165963.4(SCN1A):c.1028+21T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 1,484,396 control chromosomes in the GnomAD database, including 206,796 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 18620 hom., cov: 31)

Exomes 𝑓: 0.53 ( 188176 hom. )

Consequence

SCN1A
NM_001165963.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.295

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 links:

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

SCN1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 2-166048865-A-G is Benign according to our data. Variant chr2-166048865-A-G is described in ClinVar as [Benign]. Clinvar id is 496114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4 linkuse as main transcript	c.1028+21T>C		intron_variant		ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1 linkuse as main transcript	c.1028+21T>C		intron_variant			NM_001165963.4	P4	P35498-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.487+12735A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.487

AC:

73828

AN:

151622

Hom.:

18617

Cov.:

show subpopulations

Gnomad AFR

AF:

0.350

Gnomad AMI

AF:

0.583

Gnomad AMR

AF:

0.507

Gnomad ASJ

AF:

0.540

Gnomad EAS

AF:

0.557

Gnomad SAS

AF:

0.556

Gnomad FIN

AF:

0.536

Gnomad MID

AF:

0.446

Gnomad NFE

AF:

0.544

Gnomad OTH

AF:

0.483

GnomAD3 exomes

AF:

0.524

AC:

130644

AN:

249178

Hom.:

34610

AF XY:

0.528

AC XY:

71095

AN XY:

134714

show subpopulations

Gnomad AFR exome

AF:

0.348

Gnomad AMR exome

AF:

0.502

Gnomad ASJ exome

AF:

0.539

Gnomad EAS exome

AF:

0.576

Gnomad SAS exome

AF:

0.553

Gnomad FIN exome

AF:

0.535

Gnomad NFE exome

AF:

0.537

Gnomad OTH exome

AF:

0.514

GnomAD4 exome

AF:

0.528

AC:

704300

AN:

1332654

Hom.:

188176

Cov.:

AF XY:

0.530

AC XY:

355155

AN XY:

670414

show subpopulations

Gnomad4 AFR exome

AF:

0.332

Gnomad4 AMR exome

AF:

0.505

Gnomad4 ASJ exome

AF:

0.539

Gnomad4 EAS exome

AF:

0.554

Gnomad4 SAS exome

AF:

0.546

Gnomad4 FIN exome

AF:

0.537

Gnomad4 NFE exome

AF:

0.534

Gnomad4 OTH exome

AF:

0.519

GnomAD4 genome

AF:

0.487

AC:

73852

AN:

151742

Hom.:

18620

Cov.:

AF XY:

0.488

AC XY:

36195

AN XY:

74122

show subpopulations

Gnomad4 AFR

AF:

0.349

Gnomad4 AMR

AF:

0.508

Gnomad4 ASJ

AF:

0.540

Gnomad4 EAS

AF:

0.557

Gnomad4 SAS

AF:

0.556

Gnomad4 FIN

AF:

0.536

Gnomad4 NFE

AF:

0.544

Gnomad4 OTH

AF:

0.486

Alfa

AF:

0.522

Hom.:

25132

Bravo

AF:

0.475

Asia WGS

AF:

0.543

AC:

1887

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 05, 2016	Variant summary: The SCN1A c.1028+21T>C variant affects a non-conserved intronic nucleotide. Mutation taster predicts a benign outcome for this variant. This variant was found in 62812/119682 control chromosomes (16581 homozygotes) at a frequency of 0.5248241, which greatly exceeds the maximal expected frequency of a pathogenic SCN1A allele (0.0000179), suggesting this variant is benign. Moreover, the variant was found in an internal sample to co-occur with a pathogenic truncating SCN1A variant, further supporting neutrality. Additionally, several independent peer reviewed publications classified the variant as a polymorphism. Taken together, this variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 73% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 68. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

6.3

DANN

Benign

0.50

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over