rs41280110

Positions:

chr17-63972389-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000334.4(SCN4A):c.355G>A(p.Val119Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,613,924 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 11 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.0950

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013251126).

BP6

Variant 17-63972389-C-T is Benign according to our data. Variant chr17-63972389-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 324552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63972389-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00226 (344/152266) while in subpopulation NFE AF= 0.00382 (260/68008). AF 95% confidence interval is 0.00344. There are 3 homozygotes in gnomad4. There are 168 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4 linkuse as main transcript	c.355G>A	p.Val119Ile	missense_variant	2/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3 linkuse as main transcript	c.355G>A	p.Val119Ile	missense_variant	2/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00226

AC:

344

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000580

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00382

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00236

AC:

588

AN:

249122

Hom.:

AF XY:

0.00235

AC XY:

317

AN XY:

135160

show subpopulations

Gnomad AFR exome

AF:

0.000452

Gnomad AMR exome

AF:

0.000754

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00170

Gnomad FIN exome

AF:

0.00167

Gnomad NFE exome

AF:

0.00398

Gnomad OTH exome

AF:

0.00215

GnomAD4 exome

AF:

0.00293

AC:

4281

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00286

AC XY:

2078

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00180

Gnomad4 FIN exome

AF:

0.00202

Gnomad4 NFE exome

AF:

0.00340

Gnomad4 OTH exome

AF:

0.00283

GnomAD4 genome

AF:

0.00226

AC:

344

AN:

152266

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.00189

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.00382

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00287

Hom.:

Bravo

AF:

0.00191

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000463

AC:

ESP6500EA

AF:

0.00422

AC:

ExAC

AF:

0.00259

AC:

314

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00305

EpiControl

AF:

0.00279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SCN4A: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hyperkalemic periodic paralysis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 01, 2020

DNA sequence analysis of the SCN4A gene demonstrated a sequence change, c.355G>A, in exon 2 that results in an amino acid change, p.Val119Ile. This sequence change does not appear to have been previously described in patients with SCN4A-related disorders and has been described in the gnomAD database with a high population frequency of 0.41% in the non-Finnish European subpopulation (dbSNP rs41280110); it has been observed in one individual in the homozygous state. The p.Val119Ile change affects a poorly conserved amino acid residue located in a domain of the SCN4A protein that is not known to be functional. The p.Val119Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val119Ile change remains unknown at this time. -

Hypokalemic periodic paralysis, type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 09, 2021

- -

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 31, 2017

- -

Potassium-aggravated myotonia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Congenital myasthenic syndrome 16

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.0090

DANN

Benign

0.89

DEOGEN2

Benign

0.29

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.71

M_CAP

Benign

0.015

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.36

MutationAssessor

Benign

-1.2

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.28

REVEL

Benign

0.23

Sift

Benign

0.37

Sift4G

Benign

0.10

Polyphen

0.0

Vest4

0.11

MVP

0.49

MPC

0.20

ClinPred

0.00078

GERP RS

-0.98

Varity_R

0.049

gMVP

0.35

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

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