rs148442069

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong

The NM_001165963.4(SCN1A):c.379C>T(p.His127Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H127D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 10.0

Publications

11 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 18 uncertain in NM_001165963.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-166058573-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 190002.Status of the report is criteria_provided_single_submitter, 1 stars.

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 familial or sporadic hemiplegic migraine, myoclonic-astatic epilepsy, arthrogryposis, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, type 2, migraine, familial hemiplegic, 3, developmental and epileptic encephalopathy, 6A, familial hemiplegic migraine, generalized epilepsy with febrile seizures plus, genetic developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.831

PP5

Variant 2-166058574-G-A is Pathogenic according to our data. Variant chr2-166058574-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 582634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4 link	c.379C>T	p.His127Tyr	missense_variant	Exon 5 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.379C>T	p.His127Tyr	missense_variant	Exon 5 of 29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 link	c.379C>T	p.His127Tyr	missense_variant	Exon 4 of 28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 link	c.379C>T	p.His127Tyr	missense_variant	Exon 2 of 26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.2 link	c.379C>T	p.His127Tyr	missense_variant	Exon 4 of 28	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1396632

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698778

African (AFR)

AF:

0.00

AC:

AN:

31906

American (AMR)

AF:

0.00

AC:

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25706

East Asian (EAS)

AF:

0.00

AC:

AN:

39248

South Asian (SAS)

AF:

0.00

AC:

AN:

84854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1053364

Other (OTH)

AF:

0.00

AC:

AN:

58016

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Pathogenic:1

Jun 07, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A different missense substitution at this codon (p.His127Asp) has been reported to be de novo in individuals affected with Dravet syndrome (PMID: 21248271). This variant identified in the SCN1A gene is located in the transmembrane spanning D1-S1 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. For these reasons, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has been observed to be de novo in an individual affected with early infantile epileptic encephalopathy¬†(Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with tyrosine at codon 127 of the SCN1A protein (p.His127Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. -

Generalized epilepsy with febrile seizures plus, type 2

Pathogenic:1

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

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

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

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

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.5

.;.;.;H;H;.;H;H;H;H

PhyloP100

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.8

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

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.011

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

Polyphen

0.0080

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

Vest4

0.94, 0.92

MutPred

0.50

Gain of ubiquitination at K123 (P = 0.0599);Gain of ubiquitination at K123 (P = 0.0599);Gain of ubiquitination at K123 (P = 0.0599);Gain of ubiquitination at K123 (P = 0.0599);Gain of ubiquitination at K123 (P = 0.0599);Gain of ubiquitination at K123 (P = 0.0599);Gain of ubiquitination at K123 (P = 0.0599);Gain of ubiquitination at K123 (P = 0.0599);Gain of ubiquitination at K123 (P = 0.0599);Gain of ubiquitination at K123 (P = 0.0599);

MVP

0.98

MPC

0.79

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.98

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over