rs150154265

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBP6BS2

The NM_001165963.4(SCN1A):c.3060C>A(p.His1020Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000287 in 1,603,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. H1020D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: -0.208

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.

PM1

In a repeat II (size 272) in uniprot entity SCN1A_HUMAN there are 219 pathogenic changes around while only 11 benign (95%) in NM_001165963.4

PP2

Missense variant where missense usually causes diseases, SCN1A

BP4

Computational evidence support a benign effect (MetaRNN=0.06433785).

BP6

Variant 2-166036417-G-T is Benign according to our data. Variant chr2-166036417-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194617.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

BS2

High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4 linkuse as main transcript	c.3060C>A	p.His1020Gln	missense_variant	19/29	ENST00000674923.1
LOC102724058	NR_110598.1 linkuse as main transcript			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1 linkuse as main transcript	c.3060C>A	p.His1020Gln	missense_variant	19/29		NM_001165963.4	P4	P35498-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.487+287G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000166

AC:

AN:

241290

Hom.:

AF XY:

0.0000230

AC XY:

AN XY:

130278

show subpopulations

Gnomad AFR exome

AF:

0.0000623

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:

0.0000272

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000269

AC:

AN:

1451556

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

721506

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:

0.0000352

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000581

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 08, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 31, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2017	- -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.59

Cadd

Benign

Dann

Benign

0.64

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.62

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

M_CAP

Benign

0.013

MetaRNN

Benign

0.064

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

MetaSVM

Benign

-0.91

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.47

Polyphen

0.0

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

Vest4

0.10, 0.086, 0.085, 0.081

MutPred

0.51

.;Loss of catalytic residue at R1018 (P = 0.039);.;Loss of catalytic residue at R1018 (P = 0.039);.;.;Loss of catalytic residue at R1018 (P = 0.039);.;.;.;

MVP

0.31

MPC

0.72

ClinPred

0.037

GERP RS

-1.4

Varity_R

0.052

gMVP

0.72

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