17-63963652-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000334.4(SCN4A):c.1606+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 1,539,878 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 16 hom. )

Consequence

SCN4A
NM_000334.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.77

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:

LOC105371858 (HGNC:):

LOC105371858 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 17-63963652-C-T is Benign according to our data. Variant chr17-63963652-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255845.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 = 0.00737 (1120/152010) while in subpopulation AFR AF = 0.0205 (852/41486). AF 95% confidence interval is 0.0194. There are 12 homozygotes in GnomAd4. There are 515 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
SCN4A	NM_000334.4 link	c.1606+20G>A	intron_variant	Intron 10 of 23	ENST00000435607.3	NP_000325.4
LOC105371858	XR_001752969.2 link	n.118+338C>T	intron_variant	Intron 2 of 4
LOC105371858	XR_001752970.2 link	n.173+338C>T	intron_variant	Intron 2 of 4
LOC105371858	XR_934910.3 link	n.118+338C>T	intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3 link	c.1606+20G>A		intron_variant	Intron 10 of 23	1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes

AF:

0.00732

AC:

1112

AN:

151894

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0204

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00433

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000379

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00266

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00310

AC:

622

AN:

200510

AF XY:

0.00285

show subpopulations

Gnomad AFR exome

AF:

0.0206

Gnomad AMR exome

AF:

0.00141

Gnomad ASJ exome

AF:

0.000136

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000328

Gnomad NFE exome

AF:

0.00292

Gnomad OTH exome

AF:

0.00367

GnomAD4 exome

AF:

0.00321

AC:

4450

AN:

1387868

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

2093

AN XY:

683018

show subpopulations

African (AFR)

AF:

0.0226

AC:

720

AN:

31830

American (AMR)

AF:

0.00160

AC:

AN:

40566

Ashkenazi Jewish (ASJ)

AF:

0.0000850

AC:

AN:

23522

East Asian (EAS)

AF:

0.0000268

AC:

AN:

37354

South Asian (SAS)

AF:

0.000233

AC:

AN:

77188

European-Finnish (FIN)

AF:

0.000375

AC:

AN:

39986

Middle Eastern (MID)

AF:

0.00151

AC:

AN:

3976

European-Non Finnish (NFE)

AF:

0.00318

AC:

3421

AN:

1075928

Other (OTH)

AF:

0.00351

AC:

202

AN:

57518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

213

425

638

850

1063

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

150

300

450

600

750

<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:

0.00737

AC:

1120

AN:

152010

Hom.:

Cov.:

AF XY:

0.00693

AC XY:

515

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0205

AC:

852

AN:

41486

American (AMR)

AF:

0.00433

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000416

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000379

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00266

AC:

181

AN:

67950

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00513

Hom.:

Bravo

AF:

0.00819

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hyperkalemic periodic paralysis

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Paramyotonia congenita of Von Eulenburg;C0238357:Familial hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16;C3714580:Hypokalemic periodic paralysis, type 1

Benign:1

May 26, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely 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

-0.91

CADD

Benign

0.0090

(source)

DANN

Benign

0.72

PhyloP100

-1.8

Mutation Taster

=100/0

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

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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