rs121918807

Positions:

chr2-165994275-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM1PP2BP4_ModerateBP6BS2

The NM_001165963.4(SCN1A):c.4723C>T(p.Arg1575Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,613,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1575H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2O:2

Conservation

PhyloP100: 1.30

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 -4 ACMG points.

PM1

In a repeat IV (size 298) in uniprot entity SCN1A_HUMAN there are 297 pathogenic changes around while only 11 benign (96%) in NM_001165963.4

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=0.07794714).

BP6

Variant 2-165994275-G-A is Benign according to our data. Variant chr2-165994275-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68636.We mark this variant Likely_benign, oryginal submissions are: {not_provided=2, Uncertain_significance=4, Benign=2}. Variant chr2-165994275-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4 linkuse as main transcript	c.4723C>T	p.Arg1575Cys	missense_variant	28/29	ENST00000674923.1
LOC102724058	NR_110598.1 linkuse as main transcript	n.176-21338G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1 linkuse as main transcript	c.4723C>T	p.Arg1575Cys	missense_variant	28/29		NM_001165963.4	P4	P35498-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.193-21338G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151932

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:

0.00213

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:

0.0000718

AC:

AN:

250554

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135408

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000654

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000171

AC:

250

AN:

1461112

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

122

AN XY:

726862

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00381

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000765

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152050

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00214

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2023	Published functional studies demonstrate that R1575C may increase channel activity and act as a susceptibility allele (Ohmori et al., 2008); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This substitution is predicted to be within the transmembrane segment S2 of the fourth homologous domain; This variant is associated with the following publications: (PMID: 20675100, 33067208, 22309220, 22050978, 31719132, 18930999, 31875159, 23195492, 18031552, 21868258, 19586930, 27538648, 26311622, 22386634, 18076640, 32613771, 34661330) -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 07, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2017	- -

Severe myoclonic epilepsy in infancy

Uncertain:1Benign:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 10, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
not provided, no classification provided	literature only	Channelopathy-Associated Epilepsy Research Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

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

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.15

LIST_S2

Uncertain

0.93

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

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.078

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

MetaSVM

Uncertain

0.33

MutationAssessor

Benign

1.6

.;.;.;L;.;.;L;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.0

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

REVEL

Uncertain

0.54

Sift

Benign

0.031

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

Sift4G

Benign

0.17

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

Polyphen

0.99

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

Vest4

0.85, 0.90, 0.87, 0.83

MVP

0.96

MPC

2.0

ClinPred

0.16

GERP RS

5.9

Varity_R

0.089

gMVP

0.93

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