rs778649637

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_000334.4(SCN4A):c.1553G>A(p.Gly518Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.02

Publications

0 publications found

Variant links:

Genes affected

SCN4A (HGNC:10591): (sodium voltage-gated channel alpha subunit 4) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders. [provided by RefSeq, Jul 2008]

SCN4A Gene-Disease associations (from GenCC):

hyperkalemic periodic paralysis
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
paramyotonia congenita of Von Eulenburg
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
SCN4A-related myopathy, autosomal recessive
Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina, ClinGen
hypokalemic periodic paralysis, type 2
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
potassium-aggravated myotonia
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
congenital myasthenic syndrome 16
Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
congenital myopathy
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
congenital myopathy 22A, classic
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
acetazolamide-responsive myotonia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypokalemic periodic paralysis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
myotonia fluctuans
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
myotonia permanens
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SCN4A links:

LOC105371858 (HGNC:):

LOC105371858 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 97 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 1.5606 (below the threshold of 3.09). Trascript score misZ: 2.2224 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital myasthenic syndrome 16, paramyotonia congenita of Von Eulenburg, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, type 2, congenital myopathy, hypokalemic periodic paralysis, SCN4A-related myopathy, autosomal recessive, congenital myopathy 22A, classic, potassium-aggravated myotonia, postsynaptic congenital myasthenic syndrome, myotonia fluctuans, myotonia permanens, acetazolamide-responsive myotonia.

BP4

Computational evidence support a benign effect (MetaRNN=0.10534763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN4A	NM_000334.4 link	c.1553G>A	p.Gly518Glu	missense_variant	Exon 10 of 24	ENST00000435607.3	NP_000325.4	P35499
LOC105371858	XR_001752969.2 link	n.119-359C>T		intron_variant	Intron 2 of 4
LOC105371858	XR_001752970.2 link	n.174-359C>T		intron_variant	Intron 2 of 4
LOC105371858	XR_934910.3 link	n.118+411C>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3 link	c.1553G>A	p.Gly518Glu	missense_variant	Exon 10 of 24	1	NM_000334.4	ENSP00000396320.1		P35499

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000416

AC:

AN:

240156

AF XY:

0.00000764

show subpopulations

Gnomad AFR exome

AF:

0.0000688

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1452284

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721590

show subpopulations

African (AFR)

AF:

0.0000602

AC:

AN:

33212

American (AMR)

AF:

0.00

AC:

AN:

44216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25958

East Asian (EAS)

AF:

0.00

AC:

AN:

39274

South Asian (SAS)

AF:

0.00

AC:

AN:

85086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5468

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107508

Other (OTH)

AF:

0.00

AC:

AN:

59976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 11, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hyperkalemic periodic paralysis

Uncertain:1

Feb 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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"). ClinVar contains an entry for this variant (Variation ID: 436667). This variant has not been reported in the literature in individuals affected with SCN4A-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 518 of the SCN4A protein (p.Gly518Glu). -

Paramyotonia congenita of Von Eulenburg;C0238357:Familial hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16;C3714580:Hypokalemic periodic paralysis, type 1

Uncertain:1

Dec 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.27

DEOGEN2

Benign

0.29

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.68

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.61

M_CAP

Benign

0.055

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.4

PhyloP100

1.0

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.82

REVEL

Uncertain

0.29

Sift

Benign

0.69

Sift4G

Benign

0.16

Polyphen

0.0

Vest4

0.25

MutPred

0.26

Gain of solvent accessibility (P = 0.0596);

MVP

0.68

MPC

0.33

ClinPred

0.024

GERP RS

2.4

Varity_R

0.049

gMVP

0.24

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over