rs76894284

chr17-63957249-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000334.4(SCN4A):c.2289C>T(p.Ile763=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,613,184 control chromosomes in the GnomAD database, including 255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (20 hom., cov: 32)
  • Exomes 𝑓: 0.017 (235 hom.)
• Consequence: SCN4A NM_000334.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.00100

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 17-63957249-G-A is Benign according to our data. Variant chr17-63957249-G-A is described in ClinVar as [Benign]. Clinvar id is 130229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63957249-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.001 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0145 (2205/152324) while in subpopulation SAS AF= 0.0321 (155/4830). AF 95% confidence interval is 0.028. There are 20 homozygotes in gnomad4. There are 1048 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4	c.2289C>T	p.Ile763=	synonymous_variant	13/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3	c.2289C>T	p.Ile763=	synonymous_variant	13/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2202 AN: 152206 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00864

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0407

Gnomad EAS AF: 0.0193

Gnomad SAS AF: 0.0321

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0210

GnomAD3 exomes AF: 0.0171 AC: 4282 AN: 251096 Hom.: 57 AF XY: 0.0185 AC XY: 2508 AN XY: 135716

Gnomad AFR exome AF: 0.00746

Gnomad AMR exome AF: 0.00963

Gnomad ASJ exome AF: 0.0434

Gnomad EAS exome AF: 0.0187

Gnomad SAS exome AF: 0.0329

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0165 AC: 24122 AN: 1460860 Hom.: 235 Cov.: 32 AF XY: 0.0172 AC XY: 12511 AN XY: 726532

Gnomad4 AFR exome AF: 0.00750

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0465

Gnomad4 EAS exome AF: 0.0191

Gnomad4 SAS exome AF: 0.0330

Gnomad4 FIN exome AF: 0.00421

Gnomad4 NFE exome AF: 0.0154

Gnomad4 OTH exome AF: 0.0174

GnomAD4 genome AF: 0.0145 AC: 2205 AN: 152324 Hom.: 20 Cov.: 32 AF XY: 0.0141 AC XY: 1048 AN XY: 74478

Gnomad4 AFR AF: 0.00871

Gnomad4 AMR AF: 0.0136

Gnomad4 ASJ AF: 0.0407

Gnomad4 EAS AF: 0.0193

Gnomad4 SAS AF: 0.0321

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.0169

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0171 Hom.: 11

Bravo AF: 0.0141

Asia WGS AF: 0.0310 AC: 107 AN: 3478

EpiCase AF: 0.0179

EpiControl AF: 0.0192

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -
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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hyperkalemic periodic paralysis Benign:2

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

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

May 30, 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	-0.45
Cadd	Benign	8.5
Dann	Benign	0.82

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: rs76894284; hg19: chr17-62034609; COSMIC: COSV71125900; COSMIC: COSV71125900;