rs147352060

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000334.4(SCN4A):c.248T>C(p.Leu83Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,597,832 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.50

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: 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 -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=0.013655692).

BP6

Variant 17-63972594-A-G is Benign according to our data. Variant chr17-63972594-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 426413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00132 (201/152246) while in subpopulation AFR AF = 0.00474 (197/41550). AF 95% confidence interval is 0.0042. There are 3 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN4A	NM_000334.4 link	c.248T>C	p.Leu83Pro	missense_variant	Exon 1 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.248T>C	p.Leu83Pro	missense_variant	Exon 1 of 24	1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes

AF:

0.00129

AC:

197

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00466

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000398

AC:

AN:

220952

AF XY:

0.000242

show subpopulations

Gnomad AFR exome

AF:

0.00582

Gnomad AMR exome

AF:

0.000229

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000102

Gnomad OTH exome

AF:

0.000355

GnomAD4 exome

AF:

0.000144

AC:

208

AN:

1445586

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

717868

show subpopulations

African (AFR)

AF:

0.00487

AC:

161

AN:

33086

American (AMR)

AF:

0.000315

AC:

AN:

41258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25842

East Asian (EAS)

AF:

0.00

AC:

AN:

38958

South Asian (SAS)

AF:

0.0000951

AC:

AN:

84164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52540

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00000272

AC:

AN:

1104108

Other (OTH)

AF:

0.000351

AC:

AN:

59884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00132

AC:

201

AN:

152246

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00474

AC:

197

AN:

41550

American (AMR)

AF:

0.000261

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000373

Hom.:

Bravo

AF:

0.00163

ESP6500AA

AF:

0.00339

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000480

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 23, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SCN4A: BS2 -

Familial hyperkalemic periodic paralysis

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Benign

-0.0027

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Benign

0.068

Eigen_PC

Benign

0.15

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.65

MutationAssessor

Pathogenic

3.3

PhyloP100

7.5

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

Sift4G

Benign

0.098

Polyphen

0.092

Vest4

0.39

MVP

0.90

MPC

0.63

ClinPred

0.19

GERP RS

4.3

PromoterAI

0.025

Neutral

(source)

Varity_R

0.81

gMVP

0.90

Mutation Taster

=72/28

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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