rs185941768

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2BP4_StrongBP6

The NM_000334.4(SCN4A):c.1462G>A(p.Ala488Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000497 in 1,600,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00049 ( 0 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 0.212

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: 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:

LOC105371858 (HGNC:):

LOC105371858 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 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=0.009543866).

BP6

Variant 17-63963816-C-T is Benign according to our data. Variant chr17-63963816-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 324540.

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.1462G>A	p.Ala488Thr	missense	Exon 10 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.1462G>A	p.Ala488Thr	missense	Exon 10 of 24	ENSP00000396320.1	P35499

Frequencies

GnomAD3 genomes

AF:

0.000578

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000570

AC:

128

AN:

224430

AF XY:

0.000566

show subpopulations

Gnomad AFR exome

AF:

0.0000755

Gnomad AMR exome

AF:

0.000309

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000603

Gnomad FIN exome

AF:

0.00107

Gnomad NFE exome

AF:

0.000948

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000489

AC:

708

AN:

1447952

Hom.:

Cov.:

AF XY:

0.000505

AC XY:

363

AN XY:

719128

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33186

American (AMR)

AF:

0.000324

AC:

AN:

43200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25800

East Asian (EAS)

AF:

0.00

AC:

AN:

39104

South Asian (SAS)

AF:

0.00

AC:

AN:

83658

European-Finnish (FIN)

AF:

0.000638

AC:

AN:

51732

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000575

AC:

636

AN:

1105652

Other (OTH)

AF:

0.000351

AC:

AN:

59876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000578

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.000523

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41582

American (AMR)

AF:

0.000327

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

68036

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.000704

Hom.:

Bravo

AF:

0.000461

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000599

AC:

ExAC

AF:

0.000480

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

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)

not specified (1)

Paramyotonia congenita of Von Eulenburg (1)

Potassium-aggravated myotonia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.35

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.33

M_CAP

Benign

0.057

MetaRNN

Benign

0.0095

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.090

PhyloP100

0.21

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.2

REVEL

Benign

0.24

Sift

Benign

0.17

Sift4G

Benign

0.18

Polyphen

0.15

Vest4

0.053

MVP

0.52

MPC

0.24

ClinPred

0.024

GERP RS

-0.51

Varity_R

0.040

gMVP

0.21

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over