17-63963708-T-C

Position:

• chr17-63963708-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000334.4(SCN4A):​c.1570A>G​(p.Ser524Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.92 in 1,596,468 control chromosomes in the GnomAD database, including 675,812 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (64234 hom., cov: 33)
  • Exomes 𝑓: 0.92 (611578 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.211

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]

LOC105371858 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.298579E-7).
• BP6: Variant 17-63963708-T-C is Benign according to our data. Variant chr17-63963708-T-C is described in ClinVar as [Benign]. Clinvar id is 130228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63963708-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN4A	NM_000334.4	c.1570A>G	p.Ser524Gly	missense_variant	10/24	ENST00000435607.3	NP_000325.4
LOC105371858	XR_001752969.2	n.119-376T>C		intron_variant, non_coding_transcript_variant
LOC105371858	XR_001752970.2	n.174-376T>C		intron_variant, non_coding_transcript_variant
LOC105371858	XR_934910.3	n.118+394T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3	c.1570A>G	p.Ser524Gly	missense_variant	10/24	1	NM_000334.4	ENSP00000396320	P1

Frequencies

GnomAD3 genomes AF: 0.918 AC: 139723 AN: 152196 Hom.: 64187 Cov.: 33

Gnomad AFR AF: 0.906

Gnomad AMI AF: 0.952

Gnomad AMR AF: 0.939

Gnomad ASJ AF: 0.963

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.963

Gnomad FIN AF: 0.872

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.915

Gnomad OTH AF: 0.925

GnomAD3 exomes AF: 0.931 AC: 221561 AN: 238108 Hom.: 103297 AF XY: 0.932 AC XY: 121183 AN XY: 130012

Gnomad AFR exome AF: 0.904

Gnomad AMR exome AF: 0.964

Gnomad ASJ exome AF: 0.968

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.962

Gnomad FIN exome AF: 0.873

Gnomad NFE exome AF: 0.911

Gnomad OTH exome AF: 0.927

GnomAD4 exome AF: 0.920 AC: 1328395 AN: 1444154 Hom.: 611578 Cov.: 49 AF XY: 0.921 AC XY: 660311 AN XY: 716726

Gnomad4 AFR exome AF: 0.904

Gnomad4 AMR exome AF: 0.962

Gnomad4 ASJ exome AF: 0.970

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.960

Gnomad4 FIN exome AF: 0.873

Gnomad4 NFE exome AF: 0.913

Gnomad4 OTH exome AF: 0.929

GnomAD4 genome AF: 0.918 AC: 139826 AN: 152314 Hom.: 64234 Cov.: 33 AF XY: 0.918 AC XY: 68364 AN XY: 74468

Gnomad4 AFR AF: 0.906

Gnomad4 AMR AF: 0.939

Gnomad4 ASJ AF: 0.963

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.964

Gnomad4 FIN AF: 0.872

Gnomad4 NFE AF: 0.915

Gnomad4 OTH AF: 0.926

Alfa AF: 0.922 Hom.: 123232

Bravo AF: 0.921

TwinsUK AF: 0.912 AC: 3382

ALSPAC AF: 0.907 AC: 3497

ESP6500AA AF: 0.908 AC: 3887

ESP6500EA AF: 0.919 AC: 7806

ExAC AF: 0.926 AC: 111993

Asia WGS AF: 0.969 AC: 3370 AN: 3476

EpiCase AF: 0.925

EpiControl AF: 0.921

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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	Eurofins Ntd Llc (ga)	Apr 02, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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. -

Familial hyperkalemic periodic paralysis Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

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. -

Paramyotonia congenita of Von Eulenburg;C0238357:Familial 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

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	6.1
DANN	Benign	0.46
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.092	T
MetaRNN	Benign	8.3e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.37
Sift	Benign	0.37	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.041
MPC		0.23
ClinPred		0.0022	T
GERP RS		1.6
Varity_R		0.039
gMVP		0.21

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: rs6504191; hg19: chr17-62041068; COSMIC: COSV71128079; COSMIC: COSV71128079;