rs2070720

Positions:

• chr17-63941413-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000334.4(SCN4A):​c.4869A>G​(p.Thr1623=) 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:11
• Conservation: PhyloP100: -8.59

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 92864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63941413-T-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4	c.4869A>G	p.Thr1623=	synonymous_variant	24/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3	c.4869A>G	p.Thr1623=	synonymous_variant	24/24	1	NM_000334.4	P1

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

GnomAD3 exomes AF: 0.368 AC: 91787 AN: 249452 Hom.: 17669 AF XY: 0.362 AC XY: 48919 AN XY: 135312

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 SAS exome AF: 0.276

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

Gnomad4 AFR exome AF: 0.598

Gnomad4 AMR exome AF: 0.357

Gnomad4 ASJ exome AF: 0.396

Gnomad4 EAS exome AF: 0.427

Gnomad4 SAS exome AF: 0.278

Gnomad4 FIN exome AF: 0.359

Gnomad4 NFE exome AF: 0.356

Gnomad4 OTH exome AF: 0.377

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

Gnomad4 AFR AF: 0.590

Gnomad4 AMR AF: 0.357

Gnomad4 ASJ AF: 0.392

Gnomad4 EAS AF: 0.422

Gnomad4 SAS AF: 0.269

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.422

Alfa AF: 0.375 Hom.: 26403

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2013	- -

Hyperkalemic periodic paralysis Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Hypokalemic periodic paralysis, type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Paramyotonia congenita of Von Eulenburg;C0238357:Hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16 Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 14, 2017

- -

Potassium-aggravated myotonia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Congenital myasthenic syndrome 16 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.045
DANN	Benign	0.22

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

Other links and lift over

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