rs62070884

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19O:1

Conservation

PhyloP100: 7.91

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a repeat II (size 272) in uniprot entity SCN4A_HUMAN there are 25 pathogenic changes around while only 3 benign (89%) in NM_000334.4

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 [Likely_benign]. Clinvar id is 21153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63957197-C-T is described in Lovd as [Benign]. Variant chr17-63957197-C-T is described in Lovd as [Pathogenic]. Variant chr17-63957197-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN4A	NM_000334.4 link	c.2341G>A	p.Val781Ile	missense_variant	Exon 13 of 24	ENST00000435607.3	NP_000325.4	P35499

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3 link	c.2341G>A	p.Val781Ile	missense_variant	Exon 13 of 24	1	NM_000334.4	ENSP00000396320.1		P35499

Frequencies

GnomAD3 genomes

AF:

0.00874

AC:

1330

AN:

152186

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0106

AC:

2533

AN:

239510

Hom.:

AF XY:

0.00942

AC XY:

1212

AN XY:

128652

show subpopulations

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 SAS exome

AF:

0.00199

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.:

Cov.:

AF XY:

0.00735

AC XY:

5233

AN XY:

711532

show subpopulations

Gnomad4 AFR exome

AF:

0.00117

Gnomad4 AMR exome

AF:

0.0307

Gnomad4 ASJ exome

AF:

0.00351

Gnomad4 EAS exome

AF:

0.0239

Gnomad4 SAS exome

AF:

0.00150

Gnomad4 FIN exome

AF:

0.00851

Gnomad4 NFE exome

AF:

0.00695

Gnomad4 OTH exome

AF:

0.00541

GnomAD4 genome

AF:

0.00872

AC:

1328

AN:

152304

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

745

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00185

Gnomad4 AMR

AF:

0.0310

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.0187

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00979

Gnomad4 NFE

AF:

0.00804

Gnomad4 OTH

AF:

0.00614

Alfa

AF:

0.00812

Hom.:

Bravo

AF:

0.00920

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.00900

AC:

1093

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

- -

May 04, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 05, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN4A: BS1, BS2 -

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hyperkalemic periodic paralysis

Benign:2Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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. -

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. -

Paramyotonia congenita of Von Eulenburg;C0238357: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

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

1.6

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.93

REVEL

Pathogenic

0.73

Sift

Benign

0.051

Sift4G

Benign

0.39

Polyphen

0.89

Vest4

0.79

MPC

0.65

ClinPred

0.019

GERP RS

3.9

Varity_R

0.35

gMVP

0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over