2-165991493-G-C

Position:

chr2-165991493-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001165963.4(SCN1A):c.5782C>G(p.Arg1928Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,613,854 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 3 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 2.52

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:

LOC102724058 (HGNC:):

LOC102724058 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN1A. . Gene score misZ: 5.2206 (greater than the threshold 3.09). Trascript score misZ: 7.6022 (greater than threshold 3.09). The gene has 848 curated pathogenic missense variants (we use a threshold of 10). The gene has 89 curated benign missense variants. GenCC has associacion of the gene with 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=0.014153391).

BP6

Variant 2-165991493-G-C is Benign according to our data. Variant chr2-165991493-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 68574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165991493-G-C is described in Lovd as [Likely_benign]. Variant chr2-165991493-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00141 (214/152154) while in subpopulation AMR AF= 0.00432 (66/15266). AF 95% confidence interval is 0.00349. There are 1 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 214 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4 link	c.5782C>G	p.Arg1928Gly	missense_variant	29/29	ENST00000674923.1	NP_001159435.1	P35498-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN1A	ENST00000674923.1 link	c.5782C>G	p.Arg1928Gly	missense_variant	29/29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 link	c.5782C>G	p.Arg1928Gly	missense_variant	28/28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 link	c.5749C>G	p.Arg1917Gly	missense_variant	26/26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.1 link	c.5698C>G	p.Arg1900Gly	missense_variant	26/26	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

214

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00433

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00174

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00137

AC:

344

AN:

250686

Hom.:

AF XY:

0.00134

AC XY:

181

AN XY:

135454

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00411

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00158

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00154

AC:

2254

AN:

1461700

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

1117

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00430

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00175

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00141

AC:

214

AN:

152154

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.00432

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00174

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00137

Hom.:

Bravo

AF:

0.00178

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00143

AC:

173

EpiCase

AF:

0.00164

EpiControl

AF:

0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SCN1A: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 18413471, 26990884, 21713554, 28202706, 18056581, 18930999, 11254444, 31780880, 33108073) -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 21, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 16, 2024	- -

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

Mar 05, 2018

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

Feb 01, 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

Epilepsy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Severe myoclonic epilepsy in infancy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

.;.;.;D;.;D;.;.;.

Eigen

Benign

0.081

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.67

T;T;T;T;.;.;.;T;T

MetaRNN

Benign

0.014

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.4

.;.;.;M;.;M;.;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.1

.;.;.;N;.;N;.;N;N

REVEL

Pathogenic

0.70

Sift

Benign

0.30

.;.;.;T;.;T;.;T;T

Sift4G

Benign

0.096

.;.;.;T;.;T;.;T;T

Polyphen

0.22

.;.;.;.;B;.;B;B;.

Vest4

0.48, 0.71, 0.57, 0.45

MVP

0.96

MPC

0.92

ClinPred

0.036

GERP RS

4.9

Varity_R

0.16

gMVP

0.83

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