rs115695396

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PP3_StrongBP6_Very_StrongBA1

The NM_000334.4(SCN4A):c.2989+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00349 in 1,569,074 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 105 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 89 hom. )

Consequence

SCN4A
NM_000334.4 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 5.25

Publications

0 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: Benign. The variant received -12 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 17-63949388-C-T is Benign according to our data. Variant chr17-63949388-C-T is described in ClinVar as Benign. ClinVar VariationId is 130231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0637 is higher than 0.05.

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.2989+5G>A		splice_region intron	N/A	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.2989+5G>A		splice_region intron	N/A	ENSP00000396320.1	P35499
	SCN4A	ENST00000584310.1	TSL:4	n.312+5G>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0190

AC:

2885

AN:

152156

Hom.:

105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0660

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.00403

AC:

724

AN:

179700

AF XY:

0.00319

show subpopulations

Gnomad AFR exome

AF:

0.0611

Gnomad AMR exome

AF:

0.00293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.00231

GnomAD4 exome

AF:

0.00182

AC:

2585

AN:

1416800

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

1082

AN XY:

700874

show subpopulations

African (AFR)

AF:

0.0655

AC:

2126

AN:

32440

American (AMR)

AF:

0.00364

AC:

139

AN:

38216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25326

East Asian (EAS)

AF:

0.0000268

AC:

AN:

37318

South Asian (SAS)

AF:

0.0000369

AC:

AN:

81272

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49284

Middle Eastern (MID)

AF:

0.00456

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.0000505

AC:

AN:

1088518

Other (OTH)

AF:

0.00400

AC:

235

AN:

58722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

126

252

378

504

630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.0189

AC:

2884

AN:

152274

Hom.:

105

Cov.:

AF XY:

0.0180

AC XY:

1343

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0658

AC:

2732

AN:

41540

American (AMR)

AF:

0.00719

AC:

110

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68008

Other (OTH)

AF:

0.0133

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

144

288

432

576

720

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.00995

Hom.:

Bravo

AF:

0.0214

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Hyperkalemic periodic paralysis (2)

Congenital myasthenic syndrome 16 (1)

Hypokalemic periodic paralysis, type 2 (1)

not provided (1)

Paramyotonia congenita of Von Eulenburg (1)

Potassium-aggravated myotonia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

5.2

Mutation Taster

=83/17

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.11

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