rs144679294

Positions:

• chr2-166037833-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001165963.4(SCN1A):​c.2889T>C​(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (21 hom.)
• Consequence: SCN1A NM_001165963.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.597

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 -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
SCN1A	NM_001165963.4	c.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
SCN1A	ENST00000674923.1	c.2889T>C	p.Ala963=	synonymous_variant	18/29		NM_001165963.4	ENSP00000501589	P4
SCN1A-AS1	ENST00000651574.1	n.487+1703A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 500 AN: 152178 Hom.: 6 Cov.: 32

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

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

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

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

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SCN1A: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 10, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 09, 2012

- -

Migraine, familial hemiplegic, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This 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 submitter

clinical testing

Ambry Genetics

May 03, 2016

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. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Generalized epilepsy with febrile seizures plus, type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This 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 provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2019

This 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 submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 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

Other links and lift over

dbSNP: rs144679294; hg19: chr2-166894343;