2-165991477-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_001165963.4(SCN1A):c.5798G>A(p.Arg1933Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.677

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 Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant in the SCN1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 848 curated pathogenic missense variants (we use a threshold of 10). The gene has 89 curated benign missense variants. Gene score misZ: 5.2206 (above the threshold of 3.09). Trascript score misZ: 7.6022 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.14824611).

BP6

Variant 2-165991477-C-T is Benign according to our data. Variant chr2-165991477-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1138334.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4 link	c.5798G>A	p.Arg1933Gln	missense_variant	Exon 29 of 29	ENST00000674923.1	NP_001159435.1	P35498-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN1A	ENST00000674923.1 link	c.5798G>A	p.Arg1933Gln	missense_variant	Exon 29 of 29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 link	c.5798G>A	p.Arg1933Gln	missense_variant	Exon 28 of 28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 link	c.5765G>A	p.Arg1922Gln	missense_variant	Exon 26 of 26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.1 link	c.5714G>A	p.Arg1905Gln	missense_variant	Exon 26 of 26	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250572

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135388

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000885

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461642

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152016

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 28, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN1A c.5798G>A (p.Arg1933Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250572 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5798G>A has been reported in the literature in an individual affected with SCN1A-Related Seizure Disorder (Turkyilmaz_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Feb 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.47

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

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.044

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.93

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

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.15

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

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.2

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

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.1

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

REVEL

Uncertain

0.31

Sift

Benign

0.76

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

Sift4G

Benign

0.43

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

Polyphen

0.0050

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

Vest4

0.090, 0.11, 0.099, 0.20

MutPred

0.54

.;.;.;Gain of helix (P = 0.0854);.;Gain of helix (P = 0.0854);.;.;.;

MVP

0.81

MPC

0.83

ClinPred

0.38

GERP RS

5.8

Varity_R

0.10

gMVP

0.64

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