rs35735053

Positions:

chr2-165991411-A-G

Variant summary

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

The NM_001165963.4(SCN1A):c.5864T>C(p.Ile1955Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0015 in 1,613,784 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0082 ( 20 hom., cov: 32)

Exomes 𝑓: 0.00080 ( 16 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.39

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). GenCC has associacion of 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=0.004661292).

BP6

Variant 2-165991411-A-G is Benign according to our data. Variant chr2-165991411-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 93660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165991411-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0082 (1247/152158) while in subpopulation AFR AF= 0.0288 (1194/41530). AF 95% confidence interval is 0.0274. There are 20 homozygotes in gnomad4. There are 564 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1247 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4 linkuse as main transcript	c.5864T>C	p.Ile1955Thr	missense_variant	29/29	ENST00000674923.1	NP_001159435.1
LOC102724058	NR_110598.1 linkuse as main transcript	n.176-24202A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1 linkuse as main transcript	c.5864T>C	p.Ile1955Thr	missense_variant	29/29		NM_001165963.4	ENSP00000501589	P4	P35498-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.193-24202A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00819

AC:

1245

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0288

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00194

AC:

486

AN:

250704

Hom.:

AF XY:

0.00153

AC XY:

207

AN XY:

135472

show subpopulations

Gnomad AFR exome

AF:

0.0278

Gnomad AMR exome

AF:

0.000899

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:

0.00

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000804

AC:

1175

AN:

1461626

Hom.:

Cov.:

AF XY:

0.000700

AC XY:

509

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.0303

Gnomad4 AMR exome

AF:

0.00110

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00152

GnomAD4 genome

AF:

0.00820

AC:

1247

AN:

152158

Hom.:

Cov.:

AF XY:

0.00758

AC XY:

564

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0288

Gnomad4 AMR

AF:

0.00275

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.00954

ESP6500AA

AF:

0.0275

AC:

121

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00236

AC:

287

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 27, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2013	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 provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 25, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	SCN1A: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2016

This 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 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. -

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

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.59

DEOGEN2

Benign

0.38

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

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.11

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

MetaRNN

Benign

0.0047

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

MetaSVM

Benign

-0.53

MutationAssessor

Benign

-0.16

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

MutationTaster

Benign

0.99

N;N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.21

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

REVEL

Uncertain

0.33

Sift

Benign

0.48

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

Sift4G

Benign

0.57

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

Polyphen

0.0020

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

Vest4

0.082, 0.097, 0.10, 0.19

MVP

0.23

MPC

0.91

ClinPred

0.0070

GERP RS

4.5

Varity_R

0.095

gMVP

0.17

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