rs2227907

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000334.4(SCN4A):c.5403C>T(p.Ala1801Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,613,594 control chromosomes in the GnomAD database, including 6,704 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1801A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.12 ( 3473 hom., cov: 32)

Exomes 𝑓: 0.013 ( 3231 hom. )

Consequence

SCN4A
NM_000334.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -4.26

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 17-63940879-G-A is Benign according to our data. Variant chr17-63940879-G-A is described in ClinVar as Benign. ClinVar VariationId is 130239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.26 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN4A	NM_000334.4 link	c.5403C>T	p.Ala1801Ala	synonymous_variant	Exon 24 of 24	ENST00000435607.3	NP_000325.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3 link	c.5403C>T	p.Ala1801Ala	synonymous_variant	Exon 24 of 24	1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17671

AN:

152090

Hom.:

3461

Cov.:

show subpopulations

Gnomad AFR

AF:

0.403

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0409

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00538

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00159

Gnomad OTH

AF:

0.0794

GnomAD2 exomes

AF:

0.0311

AC:

7726

AN:

248630

AF XY:

0.0240

show subpopulations

Gnomad AFR exome

AF:

0.420

Gnomad AMR exome

AF:

0.0219

Gnomad ASJ exome

AF:

0.0131

Gnomad EAS exome

AF:

0.00122

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.00142

Gnomad OTH exome

AF:

0.0159

GnomAD4 exome

AF:

0.0128

AC:

18668

AN:

1461386

Hom.:

3231

Cov.:

AF XY:

0.0112

AC XY:

8116

AN XY:

726994

show subpopulations

African (AFR)

AF:

0.423

AC:

14142

AN:

33452

American (AMR)

AF:

0.0238

AC:

1063

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0126

AC:

328

AN:

26128

East Asian (EAS)

AF:

0.000453

AC:

AN:

39700

South Asian (SAS)

AF:

0.00343

AC:

296

AN:

86244

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53198

Middle Eastern (MID)

AF:

0.0243

AC:

140

AN:

5766

European-Non Finnish (NFE)

AF:

0.000831

AC:

924

AN:

1111846

Other (OTH)

AF:

0.0291

AC:

1756

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

690

1380

2069

2759

3449

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

394

788

1182

1576

1970

<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:

0.116

AC:

17721

AN:

152208

Hom.:

3473

Cov.:

AF XY:

0.111

AC XY:

8295

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.403

AC:

16738

AN:

41492

American (AMR)

AF:

0.0408

AC:

624

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3468

East Asian (EAS)

AF:

0.00155

AC:

AN:

5174

South Asian (SAS)

AF:

0.00518

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00159

AC:

108

AN:

68006

Other (OTH)

AF:

0.0786

AC:

166

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

568

1136

1703

2271

2839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<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:

0.0634

Hom.:

806

Bravo

AF:

0.133

Asia WGS

AF:

0.0430

AC:

149

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.00190

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Mar 07, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 28, 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

- -

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

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.14

(source)

DANN

Benign

0.47

PhyloP100

-4.3

Mutation Taster

=100/0

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