2-166048949-C-A

Position:

chr2-166048949-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2PP2PP5_ModerateBP4

The NM_001165963.4(SCN1A):c.965G>T(p.Arg322Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SCN1A
NM_001165963.4 missense, splice_region

Scores

Splicing: ADA: 0.8400

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 0.526

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

PP5

Variant 2-166048949-C-A is Pathogenic according to our data. Variant chr2-166048949-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 68584.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.36479402). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4 linkuse as main transcript	c.965G>T	p.Arg322Ile	missense_variant, splice_region_variant	10/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1 linkuse as main transcript	c.965G>T	p.Arg322Ile	missense_variant, splice_region_variant	10/29		NM_001165963.4	ENSP00000501589	P4	P35498-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.487+12819C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1443262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719156

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2023

This missense change has been observed in individual(s) with Dravet syndrome (PMID: 17561957, 18930999, 30146492). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 322 of the SCN1A protein (p.Arg322Ile). ClinVar contains an entry for this variant (Variation ID: 68584). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN1A function (PMID: 30146492). 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 C15"). -

Severe myoclonic epilepsy in infancy

Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Pathogenic

0.81

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

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.89

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

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.36

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

MetaSVM

Uncertain

0.24

MutationAssessor

Benign

0.81

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.6

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

REVEL

Uncertain

0.61

Sift

Uncertain

0.022

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

Sift4G

Benign

0.095

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

Polyphen

0.022, 0.0040

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

Vest4

0.57, 0.57, 0.58, 0.57

MutPred

0.59

Gain of loop (P = 0.0111);Gain of loop (P = 0.0111);Gain of loop (P = 0.0111);Gain of loop (P = 0.0111);Gain of loop (P = 0.0111);Gain of loop (P = 0.0111);Gain of loop (P = 0.0111);Gain of loop (P = 0.0111);Gain of loop (P = 0.0111);Gain of loop (P = 0.0111);

MVP

0.99

MPC

1.3

ClinPred

0.55

GERP RS

3.5

Varity_R

0.11

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.84

dbscSNV1_RF

Pathogenic

0.76

SpliceAI score (max)

0.17

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