17-63963708-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000334.4(SCN4A):c.1570A>G(p.Ser524Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.92 in 1,596,468 control chromosomes in the GnomAD database, including 675,812 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.92 ( 64234 hom., cov: 33)

Exomes 𝑓: 0.92 ( 611578 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.211

Publications

33 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: Benign. The variant received -19 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 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=8.298579E-7).

BP6

Variant 17-63963708-T-C is Benign according to our data. Variant chr17-63963708-T-C is described in ClinVar as Benign. ClinVar VariationId is 130228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SCN4A	NM_000334.4 link	c.1570A>G	p.Ser524Gly	missense_variant	Exon 10 of 24	ENST00000435607.3	NP_000325.4
LOC105371858	XR_001752969.2 link	n.119-376T>C		intron_variant	Intron 2 of 4
LOC105371858	XR_001752970.2 link	n.174-376T>C		intron_variant	Intron 2 of 4
LOC105371858	XR_934910.3 link	n.118+394T>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3 link	c.1570A>G	p.Ser524Gly	missense_variant	Exon 10 of 24	1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes

AF:

0.918

AC:

139723

AN:

152196

Hom.:

64187

Cov.:

show subpopulations

Gnomad AFR

AF:

0.906

Gnomad AMI

AF:

0.952

Gnomad AMR

AF:

0.939

Gnomad ASJ

AF:

0.963

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.963

Gnomad FIN

AF:

0.872

Gnomad MID

AF:

0.962

Gnomad NFE

AF:

0.915

Gnomad OTH

AF:

0.925

GnomAD2 exomes

AF:

0.931

AC:

221561

AN:

238108

AF XY:

0.932

show subpopulations

Gnomad AFR exome

AF:

0.904

Gnomad AMR exome

AF:

0.964

Gnomad ASJ exome

AF:

0.968

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.873

Gnomad NFE exome

AF:

0.911

Gnomad OTH exome

AF:

0.927

GnomAD4 exome

AF:

0.920

AC:

1328395

AN:

1444154

Hom.:

611578

Cov.:

AF XY:

0.921

AC XY:

660311

AN XY:

716726

show subpopulations

African (AFR)

AF:

0.904

AC:

29834

AN:

32990

American (AMR)

AF:

0.962

AC:

42280

AN:

43950

Ashkenazi Jewish (ASJ)

AF:

0.970

AC:

25097

AN:

25870

East Asian (EAS)

AF:

1.00

AC:

38860

AN:

38876

South Asian (SAS)

AF:

0.960

AC:

81422

AN:

84808

European-Finnish (FIN)

AF:

0.873

AC:

43732

AN:

50084

Middle Eastern (MID)

AF:

0.947

AC:

4811

AN:

5082

European-Non Finnish (NFE)

AF:

0.913

AC:

1007025

AN:

1102910

Other (OTH)

AF:

0.929

AC:

55334

AN:

59584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

5155

10310

15464

20619

25774

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21456

42912

64368

85824

107280

<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:

0.918

AC:

139826

AN:

152314

Hom.:

64234

Cov.:

AF XY:

0.918

AC XY:

68364

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.906

AC:

37658

AN:

41566

American (AMR)

AF:

0.939

AC:

14365

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.963

AC:

3342

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5170

AN:

5174

South Asian (SAS)

AF:

0.964

AC:

4654

AN:

4830

European-Finnish (FIN)

AF:

0.872

AC:

9257

AN:

10614

Middle Eastern (MID)

AF:

0.963

AC:

283

AN:

294

European-Non Finnish (NFE)

AF:

0.915

AC:

62270

AN:

68036

Other (OTH)

AF:

0.926

AC:

1959

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

606

1213

1819

2426

3032

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

910

1820

2730

3640

4550

<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:

0.922

Hom.:

177365

Bravo

AF:

0.921

TwinsUK

AF:

0.912

AC:

3382

ALSPAC

AF:

0.907

AC:

3497

ESP6500AA

AF:

0.908

AC:

3887

ESP6500EA

AF:

0.919

AC:

7806

ExAC

AF:

0.926

AC:

111993

Asia WGS

AF:

0.969

AC:

3370

AN:

3476

EpiCase

AF:

0.925

EpiControl

AF:

0.921

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 05, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 02, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 09, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial hyperkalemic periodic paralysis

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypokalemic periodic paralysis, type 2

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Paramyotonia congenita of Von Eulenburg

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Potassium-aggravated myotonia

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Congenital myasthenic syndrome 16

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.32

CADD

Benign

6.1

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.25

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.092

MetaRNN

Benign

8.3e-7

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.0

PhyloP100

0.21

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.54

REVEL

Uncertain

0.37

Sift

Benign

0.37

Sift4G

Benign

0.24

Polyphen

0.0

Vest4

0.041

MPC

0.23

ClinPred

0.0022

GERP RS

1.6

Varity_R

0.039

gMVP

0.21

Mutation Taster

=99/1

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over