17-63942988-T-C

Variant names:

• chr17-63942988-T-C
• rs2058194
• NM_000334.4:c.4126A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000334.4(SCN4A):​c.4126A>G​(p.Asn1376Asp) variant causes a missense change. The variant allele was found at a frequency of 0.534 in 1,613,618 control chromosomes in the GnomAD database, including 233,301 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1376T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.59 (27022 hom., cov: 32)
  • Exomes 𝑓: 0.53 (206279 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.06
• Publications: 51 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 -17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000334.4
• 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 congenital myasthenic syndrome 16, paramyotonia congenita of Von Eulenburg, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, type 2, congenital myopathy, hypokalemic periodic paralysis, SCN4A-related myopathy, autosomal recessive, congenital myopathy 22A, classic, potassium-aggravated myotonia, postsynaptic congenital myasthenic syndrome, myotonia fluctuans, myotonia permanens, acetazolamide-responsive myotonia.
• BP4: Computational evidence support a benign effect (MetaRNN=6.990708E-6).
• BP6: Variant 17-63942988-T-C is Benign according to our data. Variant chr17-63942988-T-C is described in ClinVar as Benign. ClinVar VariationId is 130236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.726 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.4126A>G	p.Asn1376Asp	missense	Exon 23 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.4126A>G	p.Asn1376Asp	missense	Exon 23 of 24	ENSP00000396320.1

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89335 AN: 151984 Hom.: 26984 Cov.: 32

Gnomad AFR AF: 0.733

Gnomad AMI AF: 0.656

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.599

GnomAD2 exomes AF: 0.523 AC: 131470 AN: 251184 AF XY: 0.518

Gnomad AFR exome AF: 0.734

Gnomad AMR exome AF: 0.493

Gnomad ASJ exome AF: 0.596

Gnomad EAS exome AF: 0.511

Gnomad FIN exome AF: 0.509

Gnomad NFE exome AF: 0.534

Gnomad OTH exome AF: 0.546

GnomAD4 exome AF: 0.528 AC: 771980 AN: 1461516 Hom.: 206279 Cov.: 53 AF XY: 0.525 AC XY: 381860 AN XY: 727046

African (AFR) AF: 0.739 AC: 24736 AN: 33478

American (AMR) AF: 0.495 AC: 22157 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 15758 AN: 26136

East Asian (EAS) AF: 0.501 AC: 19887 AN: 39700

South Asian (SAS) AF: 0.395 AC: 34088 AN: 86254

European-Finnish (FIN) AF: 0.510 AC: 27258 AN: 53402

Middle Eastern (MID) AF: 0.643 AC: 3711 AN: 5768

European-Non Finnish (NFE) AF: 0.532 AC: 591857 AN: 1111686

Other (OTH) AF: 0.539 AC: 32528 AN: 60370

GnomAD4 genome AF: 0.588 AC: 89426 AN: 152102 Hom.: 27022 Cov.: 32 AF XY: 0.581 AC XY: 43202 AN XY: 74354

African (AFR) AF: 0.733 AC: 30420 AN: 41484

American (AMR) AF: 0.518 AC: 7924 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 2051 AN: 3468

East Asian (EAS) AF: 0.512 AC: 2648 AN: 5174

South Asian (SAS) AF: 0.391 AC: 1888 AN: 4826

European-Finnish (FIN) AF: 0.520 AC: 5499 AN: 10578

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.544 AC: 36942 AN: 67970

Other (OTH) AF: 0.599 AC: 1264 AN: 2110

Alfa AF: 0.558 Hom.: 92436

Bravo AF: 0.597

TwinsUK AF: 0.536 AC: 1989

ALSPAC AF: 0.527 AC: 2031

ESP6500AA AF: 0.731 AC: 3221

ESP6500EA AF: 0.532 AC: 4574

ExAC AF: 0.523 AC: 63556

Asia WGS AF: 0.461 AC: 1608 AN: 3478

EpiCase AF: 0.556

EpiControl AF: 0.557

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 02, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 25, 2021

Athena Diagnostics

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
AlphaMissense	Benign	0.039
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.61
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0000070	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.8	N
PhyloP100		5.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	3.7	N
REVEL	Uncertain	0.33
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.052
MPC		0.29
ClinPred		0.0014	T
GERP RS		3.9
Varity_R		0.23
gMVP		0.10
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2058194; hg19: chr17-62020348; COSMIC: COSV71125817; COSMIC: COSV71125817;