17-63941413-T-C

Variant names:

• chr17-63941413-T-C
• rs2070720
• NM_000334.4:c.4869A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000334.4(SCN4A):​c.4869A>G​(p.Thr1623Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,613,542 control chromosomes in the GnomAD database, including 111,831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14695 hom., cov: 30)
  • Exomes 𝑓: 0.36 (97136 hom.)
• Consequence: SCN4A NM_000334.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -8.59
• Publications: 39 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 17-63941413-T-C is Benign according to our data. Variant chr17-63941413-T-C is described in ClinVar as Benign. ClinVar VariationId is 92864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.584 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4A	NM_000334.4	MANE Select	c.4869A>G	p.Thr1623Thr	synonymous	Exon 24 of 24	NP_000325.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4A	ENST00000435607.3	TSL:1 MANE Select	c.4869A>G	p.Thr1623Thr	synonymous	Exon 24 of 24	ENSP00000396320.1

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64625 AN: 151690 Hom.: 14676 Cov.: 30

Gnomad AFR AF: 0.591

Gnomad AMI AF: 0.461

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.419

GnomAD2 exomes AF: 0.368 AC: 91787 AN: 249452 AF XY: 0.362

Gnomad AFR exome AF: 0.590

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.397

Gnomad EAS exome AF: 0.423

Gnomad FIN exome AF: 0.361

Gnomad NFE exome AF: 0.354

Gnomad OTH exome AF: 0.383

GnomAD4 exome AF: 0.361 AC: 527355 AN: 1461734 Hom.: 97136 Cov.: 49 AF XY: 0.358 AC XY: 260670 AN XY: 727168

African (AFR) AF: 0.598 AC: 20026 AN: 33476

American (AMR) AF: 0.357 AC: 15970 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 10357 AN: 26136

East Asian (EAS) AF: 0.427 AC: 16937 AN: 39696

South Asian (SAS) AF: 0.278 AC: 23936 AN: 86254

European-Finnish (FIN) AF: 0.359 AC: 19173 AN: 53406

Middle Eastern (MID) AF: 0.440 AC: 2536 AN: 5768

European-Non Finnish (NFE) AF: 0.356 AC: 395636 AN: 1111904

Other (OTH) AF: 0.377 AC: 22784 AN: 60382

GnomAD4 genome AF: 0.426 AC: 64701 AN: 151808 Hom.: 14695 Cov.: 30 AF XY: 0.420 AC XY: 31168 AN XY: 74164

African (AFR) AF: 0.590 AC: 24428 AN: 41372

American (AMR) AF: 0.357 AC: 5454 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1357 AN: 3466

East Asian (EAS) AF: 0.422 AC: 2172 AN: 5146

South Asian (SAS) AF: 0.269 AC: 1291 AN: 4804

European-Finnish (FIN) AF: 0.370 AC: 3898 AN: 10524

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24670 AN: 67928

Other (OTH) AF: 0.422 AC: 887 AN: 2102

Alfa AF: 0.385 Hom.: 40920

Bravo AF: 0.436

Asia WGS AF: 0.367 AC: 1278 AN: 3478

EpiCase AF: 0.368

EpiControl AF: 0.371

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Mar 09, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 03, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hyperkalemic periodic paralysis Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Mar 03, 2015

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

Hypokalemic periodic paralysis, type 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Paramyotonia congenita of Von Eulenburg Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Potassium-aggravated myotonia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Congenital myasthenic syndrome 16 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.045
DANN	Benign	0.22
PhyloP100		-8.6
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2070720; hg19: chr17-62018773; COSMIC: COSV71126065;