rs79893125

chr17-63951646-A-Gchr17-63951646-A-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.2631T>C(p.Asp877=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0298 in 1,603,246 control chromosomes in the GnomAD database, including 3,096 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (1496 hom., cov: 32)
  • Exomes 𝑓: 0.024 (1600 hom.)
• Consequence: SCN4A NM_000334.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.80

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=-0.9).
• BP6: Variant 17-63951646-A-G is Benign according to our data. Variant chr17-63951646-A-G is described in ClinVar as [Benign]. Clinvar id is 92861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63951646-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4	c.2631T>C	p.Asp877=	synonymous_variant	14/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3	c.2631T>C	p.Asp877=	synonymous_variant	14/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes AF: 0.0874 AC: 13270 AN: 151798 Hom.: 1489 Cov.: 32

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.0295

Gnomad FIN AF: 0.00359

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0648

GnomAD3 exomes AF: 0.0349 AC: 8000 AN: 229282 Hom.: 520 AF XY: 0.0322 AC XY: 4007 AN XY: 124550

Gnomad AFR exome AF: 0.265

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0446

Gnomad EAS exome AF: 0.0164

Gnomad SAS exome AF: 0.0305

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.0176

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0238 AC: 34538 AN: 1451330 Hom.: 1600 Cov.: 32 AF XY: 0.0233 AC XY: 16809 AN XY: 721212

Gnomad4 AFR exome AF: 0.275

Gnomad4 AMR exome AF: 0.0245

Gnomad4 ASJ exome AF: 0.0468

Gnomad4 EAS exome AF: 0.0137

Gnomad4 SAS exome AF: 0.0301

Gnomad4 FIN exome AF: 0.00424

Gnomad4 NFE exome AF: 0.0158

Gnomad4 OTH exome AF: 0.0340

GnomAD4 genome AF: 0.0876 AC: 13307 AN: 151916 Hom.: 1496 Cov.: 32 AF XY: 0.0845 AC XY: 6274 AN XY: 74244

Gnomad4 AFR AF: 0.265

Gnomad4 AMR AF: 0.0387

Gnomad4 ASJ AF: 0.0409

Gnomad4 EAS AF: 0.0166

Gnomad4 SAS AF: 0.0297

Gnomad4 FIN AF: 0.00359

Gnomad4 NFE AF: 0.0175

Gnomad4 OTH AF: 0.0641

Alfa AF: 0.0400 Hom.: 225

Bravo AF: 0.0976

Asia WGS AF: 0.0450 AC: 158 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 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	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Hyperkalemic periodic paralysis Benign:2

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. -
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 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. -

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	-0.90
Cadd	Benign	0.013
Dann	Benign	0.40

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: rs79893125; hg19: chr17-62029006;