2-165991466-G-C

Position:

chr2-165991466-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4BP6

The NM_001165963.4(SCN1A):c.5809C>G(p.Gln1937Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,708 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.02

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 (HGNC:):

SCN1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.271094).

BP6

Variant 2-165991466-G-C is Benign according to our data. Variant chr2-165991466-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 450573.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4 linkuse as main transcript	c.5809C>G	p.Gln1937Glu	missense_variant	29/29	ENST00000674923.1	NP_001159435.1	P35498-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN1A	ENST00000674923.1 linkuse as main transcript	c.5809C>G	p.Gln1937Glu	missense_variant	29/29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 linkuse as main transcript	c.5809C>G	p.Gln1937Glu	missense_variant	28/28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 linkuse as main transcript	c.5776C>G	p.Gln1926Glu	missense_variant	26/26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.1 linkuse as main transcript	c.5725C>G	p.Gln1909Glu	missense_variant	26/26	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461668

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727138

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 10, 2021

Not observed at significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This substitution is predicted to be within the C-terminal cytoplasmic domain -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Uncertain

0.45

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

Eigen

Benign

-0.074

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.066

MetaRNN

Benign

0.27

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

MetaSVM

Uncertain

0.41

MutationAssessor

Pathogenic

2.9

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

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.87

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

REVEL

Uncertain

0.30

Sift

Benign

0.12

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

Sift4G

Benign

0.61

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

Polyphen

0.0050

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

Vest4

0.33, 0.43, 0.42, 0.45

MutPred

0.42

.;.;.;Gain of loop (P = 0.0166);.;Gain of loop (P = 0.0166);.;.;.;

MVP

0.92

MPC

0.78

ClinPred

0.67

GERP RS

5.8

Varity_R

0.17

gMVP

0.45

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