rs7218917

chr17-63968195-G-Achr17-63968195-G-Cchr17-63968195-G-T

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.864C>T(p.Asn288=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,613,920 control chromosomes in the GnomAD database, including 1,454 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (610 hom., cov: 32)
  • Exomes 𝑓: 0.020 (844 hom.)
• Consequence: SCN4A NM_000334.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.38

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=-0.87).
• BP6: Variant 17-63968195-G-A is Benign according to our data. Variant chr17-63968195-G-A is described in ClinVar as [Benign]. Clinvar id is 130241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63968195-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4	c.864C>T	p.Asn288=	synonymous_variant	6/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3	c.864C>T	p.Asn288=	synonymous_variant	6/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes AF: 0.0592 AC: 8996 AN: 152088 Hom.: 607 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.0233

Gnomad SAS AF: 0.0352

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0503

GnomAD3 exomes AF: 0.0288 AC: 7181 AN: 249308 Hom.: 293 AF XY: 0.0275 AC XY: 3713 AN XY: 135230

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0174

Gnomad ASJ exome AF: 0.0446

Gnomad EAS exome AF: 0.0205

Gnomad SAS exome AF: 0.0343

Gnomad FIN exome AF: 0.00473

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.0246

GnomAD4 exome AF: 0.0201 AC: 29445 AN: 1461714 Hom.: 844 Cov.: 32 AF XY: 0.0203 AC XY: 14779 AN XY: 727138

Gnomad4 AFR exome AF: 0.175

Gnomad4 AMR exome AF: 0.0193

Gnomad4 ASJ exome AF: 0.0481

Gnomad4 EAS exome AF: 0.0298

Gnomad4 SAS exome AF: 0.0357

Gnomad4 FIN exome AF: 0.00573

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.0284

GnomAD4 genome AF: 0.0593 AC: 9026 AN: 152206 Hom.: 610 Cov.: 32 AF XY: 0.0581 AC XY: 4328 AN XY: 74432

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.0322

Gnomad4 ASJ AF: 0.0421

Gnomad4 EAS AF: 0.0233

Gnomad4 SAS AF: 0.0352

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.0150

Gnomad4 OTH AF: 0.0498

Alfa AF: 0.0287 Hom.: 212

Bravo AF: 0.0658

Asia WGS AF: 0.0440 AC: 154 AN: 3478

EpiCase AF: 0.0190

EpiControl AF: 0.0171

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 08, 2021	- -

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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

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

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. -

Congenital myasthenic syndrome 16 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	2.7
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7218917; hg19: chr17-62045555;