rs72851170

chr17-63945022-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000334.4(SCN4A):c.3759C>T(p.Ala1253=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 1,613,792 control chromosomes in the GnomAD database, including 573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (42 hom., cov: 32)
  • Exomes 𝑓: 0.025 (531 hom.)
• Consequence: SCN4A NM_000334.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.27

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=-0.55).
• BP6: Variant 17-63945022-G-A is Benign according to our data. Variant chr17-63945022-G-A is described in ClinVar as [Benign]. Clinvar id is 130235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63945022-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.28 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.019 (2890/152252) while in subpopulation NFE AF= 0.028 (1905/68008). AF 95% confidence interval is 0.027. There are 42 homozygotes in gnomad4. There are 1416 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 42 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4	c.3759C>T	p.Ala1253=	synonymous_variant	20/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3	c.3759C>T	p.Ala1253=	synonymous_variant	20/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2893 AN: 152134 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00994

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0461

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0280

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.0193 AC: 4815 AN: 248998 Hom.: 71 AF XY: 0.0199 AC XY: 2688 AN XY: 135084

Gnomad AFR exome AF: 0.00407

Gnomad AMR exome AF: 0.00667

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00559

Gnomad FIN exome AF: 0.0487

Gnomad NFE exome AF: 0.0267

Gnomad OTH exome AF: 0.0222

GnomAD4 exome AF: 0.0245 AC: 35820 AN: 1461540 Hom.: 531 Cov.: 31 AF XY: 0.0241 AC XY: 17524 AN XY: 727056

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.00738

Gnomad4 ASJ exome AF: 0.0163

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00617

Gnomad4 FIN exome AF: 0.0472

Gnomad4 NFE exome AF: 0.0274

Gnomad4 OTH exome AF: 0.0228

GnomAD4 genome AF: 0.0190 AC: 2890 AN: 152252 Hom.: 42 Cov.: 32 AF XY: 0.0190 AC XY: 1416 AN XY: 74448

Gnomad4 AFR AF: 0.00525

Gnomad4 AMR AF: 0.00993

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0461

Gnomad4 NFE AF: 0.0280

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0239 Hom.: 16

Bravo AF: 0.0157

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0261

EpiControl AF: 0.0220

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 11, 2020	- -

Hyperkalemic periodic paralysis Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 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

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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- -

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	-0.55
Cadd	Benign	0.89
Dann	Benign	0.66

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

Other links and lift over

dbSNP: rs72851170; hg19: chr17-62022382;