rs62070884

Variant names:

• chr17-63957197-C-T
• rs62070884
• NM_000334.4:c.2341G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000334.4(SCN4A):​c.2341G>A​(p.Val781Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00771 in 1,590,850 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (70 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 7.91
• Publications: 21 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 repeat II (size 272) in uniprot entity SCN4A_HUMAN there are 27 pathogenic changes around while only 3 benign (90%) 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=0.015130967).
• BP6: Variant 17-63957197-C-T is Benign according to our data. Variant chr17-63957197-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00872 (1328/152304) while in subpopulation AMR AF = 0.031 (474/15286). AF 95% confidence interval is 0.0287. There are 7 homozygotes in GnomAd4. There are 745 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN4A	NM_000334.4	c.2341G>A	p.Val781Ile	missense_variant	Exon 13 of 24	ENST00000435607.3	NP_000325.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3	c.2341G>A	p.Val781Ile	missense_variant	Exon 13 of 24	1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes AF: 0.00874 AC: 1330 AN: 152186 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0311

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0187

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00979

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00804

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.0106 AC: 2533 AN: 239510 AF XY: 0.00942

Gnomad AFR exome AF: 0.00192

Gnomad AMR exome AF: 0.0304

Gnomad ASJ exome AF: 0.00310

Gnomad EAS exome AF: 0.0189

Gnomad FIN exome AF: 0.00842

Gnomad NFE exome AF: 0.00764

Gnomad OTH exome AF: 0.00667

GnomAD4 exome AF: 0.00761 AC: 10941 AN: 1438546 Hom.: 70 Cov.: 31 AF XY: 0.00735 AC XY: 5233 AN XY: 711532

African (AFR) AF: 0.00117 AC: 39 AN: 33226

American (AMR) AF: 0.0307 AC: 1355 AN: 44080

Ashkenazi Jewish (ASJ) AF: 0.00351 AC: 87 AN: 24766

East Asian (EAS) AF: 0.0239 AC: 940 AN: 39340

South Asian (SAS) AF: 0.00150 AC: 125 AN: 83268

European-Finnish (FIN) AF: 0.00851 AC: 448 AN: 52640

Middle Eastern (MID) AF: 0.00141 AC: 8 AN: 5672

European-Non Finnish (NFE) AF: 0.00695 AC: 7618 AN: 1096230

Other (OTH) AF: 0.00541 AC: 321 AN: 59324

GnomAD4 genome AF: 0.00872 AC: 1328 AN: 152304 Hom.: 7 Cov.: 32 AF XY: 0.0100 AC XY: 745 AN XY: 74474

African (AFR) AF: 0.00185 AC: 77 AN: 41570

American (AMR) AF: 0.0310 AC: 474 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.0187 AC: 97 AN: 5178

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00979 AC: 104 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00804 AC: 547 AN: 68028

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00791 Hom.: 14

Bravo AF: 0.00920

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00900 AC: 1093

Asia WGS AF: 0.00635 AC: 23 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jul 05, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 16, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:5

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN4A: BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial hyperkalemic periodic paralysis Benign:2 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hypokalemic periodic paralysis, type 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Joubert syndrome 17 Benign:1

-

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Val781Ile variant in SCN4A has been identified in 2 individuals with hyperkalaemic periodic paralysis (PMID: 7695243, 18046642), and has been identified in >2% of Latino chromosomes and 9 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Val781Ile variant may not impact protein function (PMID: 9266738). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for hyperkalaemic periodic paralysis. -

Paramyotonia congenita of Von Eulenburg Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Potassium-aggravated myotonia Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Congenital myasthenic syndrome 16 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Apr 16, 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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.93	N
REVEL	Pathogenic	0.73
Sift	Benign	0.051	T
Sift4G	Benign	0.39	T
Polyphen		0.89	P
Vest4		0.79
MPC		0.65
ClinPred		0.019	T
GERP RS		3.9
Varity_R		0.35
gMVP		0.63
Mutation Taster		=88/12	polymorphism

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: rs62070884; hg19: chr17-62034557; COSMIC: COSV107528634; COSMIC: COSV107528634;