rs758511540

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_000334.4(SCN4A):c.5482C>T(p.Arg1828Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000189 in 1,588,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1828S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 0.822

Publications

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

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 SCN4A-related myopathy, autosomal recessive, hyperkalemic periodic paralysis, paramyotonia congenita of Von Eulenburg, congenital myasthenic syndrome 16, acetazolamide-responsive myotonia, myotonia permanens, hypokalemic periodic paralysis, type 2, potassium-aggravated myotonia, congenital myopathy 22A, classic, congenital myopathy, myotonia fluctuans, postsynaptic congenital myasthenic syndrome, hypokalemic periodic paralysis.

BP4

Computational evidence support a benign effect (MetaRNN=0.16975689).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000334.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4A	NM_000334.4	MANE Select	c.5482C>T	p.Arg1828Cys	missense	Exon 24 of 24	NP_000325.4	P35499

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4A	ENST00000435607.3	TSL:1 MANE Select	c.5482C>T	p.Arg1828Cys	missense	Exon 24 of 24	ENSP00000396320.1	P35499

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152220

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000426

AC:

AN:

234634

AF XY:

0.0000392

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000576

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000653

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000181

AC:

AN:

1436620

Hom.:

Cov.:

AF XY:

0.0000155

AC XY:

AN XY:

711796

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31906

American (AMR)

AF:

0.0000483

AC:

AN:

41442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24994

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39300

South Asian (SAS)

AF:

0.0000238

AC:

AN:

84098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52656

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.0000146

AC:

AN:

1097544

Other (OTH)

AF:

0.0000678

AC:

AN:

59018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

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

AF:

0.0000263

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000455

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000496

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyperkalemic periodic paralysis (2)

not provided (2)

Congenital myasthenic syndrome 16 (1)

Hypokalemic periodic paralysis, type 2 (1)

Paramyotonia congenita of Von Eulenburg (1)

Paramyotonia congenita of Von Eulenburg;C0238357:Hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16;C5830453:Congenital myopathy 22A, classic;C5830501:Congenital myopathy 22B, severe fetal (1)

Potassium-aggravated myotonia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.17

MetaSVM

Uncertain

-0.085

MutationAssessor

Benign

0.0

PhyloP100

0.82

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.38

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.059

Polyphen

0.0060

Vest4

0.21

MutPred

0.28

Loss of MoRF binding (P = 0.0183)

MVP

0.77

MPC

0.68

ClinPred

0.086

GERP RS

3.3

Varity_R

0.11

gMVP

0.38

Mutation Taster

=81/19

polymorphism

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over