chr17-63971859-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000334.4(SCN4A):c.483-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,503,966 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00024 ( 3 hom. )

Consequence

SCN4A
NM_000334.4 intron

Scores

Splicing: ADA: 0.000008939

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.152

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: 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 17-63971859-G-A is Benign according to our data. Variant chr17-63971859-G-A is described in ClinVar as Benign. ClinVar VariationId is 758817.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000158 (19/120524) while in subpopulation SAS AF = 0.00516 (19/3682). AF 95% confidence interval is 0.00338. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN4A	NM_000334.4 link	c.483-9C>T		intron_variant	Intron 3 of 23	ENST00000435607.3	NP_000325.4	P35499

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3 link	c.483-9C>T		intron_variant	Intron 3 of 23	1	NM_000334.4	ENSP00000396320.1		P35499

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

120402

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00515

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000483

AC:

115

AN:

238328

AF XY:

0.000656

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000600

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000354

GnomAD4 exome

AF:

0.000236

AC:

326

AN:

1383442

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

230

AN XY:

684624

show subpopulations

African (AFR)

AF:

0.0000315

AC:

AN:

31718

American (AMR)

AF:

0.00

AC:

AN:

40576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24598

East Asian (EAS)

AF:

0.0000270

AC:

AN:

36974

South Asian (SAS)

AF:

0.00452

AC:

316

AN:

69960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49318

Middle Eastern (MID)

AF:

0.000182

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

9.36e-7

AC:

AN:

1068368

Other (OTH)

AF:

0.000106

AC:

AN:

56424

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000158

AC:

AN:

120524

Hom.:

Cov.:

AF XY:

0.000252

AC XY:

AN XY:

59608

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32114

American (AMR)

AF:

0.00

AC:

AN:

12026

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2722

East Asian (EAS)

AF:

0.00

AC:

AN:

4254

South Asian (SAS)

AF:

0.00516

AC:

AN:

3682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53784

Other (OTH)

AF:

0.00

AC:

AN:

1562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

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:

0.00

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial hyperkalemic periodic paralysis

Benign:1

Oct 22, 2024

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

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

-0.15

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000089

dbscSNV1_RF

Benign

0.0080

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

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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