17-63971875-A-G

Variant names:

• chr17-63971875-A-G
• rs9892013
• NM_000334.4:c.483-25T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000334.4(SCN4A):​c.483-25T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.984 in 1,612,722 control chromosomes in the GnomAD database, including 780,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74182 hom., cov: 29)
  • Exomes 𝑓: 0.98 (706059 hom.)
• Consequence: SCN4A NM_000334.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.453
• Publications: 8 publications found

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]

SCN4A Gene-Disease associations (from GenCC):

• hyperkalemic periodic paralysis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• paramyotonia congenita of Von Eulenburg

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• SCN4A-related myopathy, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• hypokalemic periodic paralysis, type 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• potassium-aggravated myotonia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 16

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital myopathy

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• congenital myopathy 22A, classic

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• acetazolamide-responsive myotonia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypokalemic periodic paralysis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myotonia fluctuans

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myotonia permanens

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-63971875-A-G is Benign according to our data. Variant chr17-63971875-A-G is described in ClinVar as Benign. ClinVar VariationId is 255856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000334.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4A	NM_000334.4	MANE Select	c.483-25T>C		intron	N/A	NP_000325.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4A	ENST00000435607.3	TSL:1 MANE Select	c.483-25T>C		intron	N/A	ENSP00000396320.1

Frequencies

GnomAD3 genomes AF: 0.988 AC: 150084 AN: 151964 Hom.: 74124 Cov.: 29

Gnomad AFR AF: 0.997

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 0.994

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.991

Gnomad FIN AF: 0.970

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.982

Gnomad OTH AF: 0.989

GnomAD2 exomes AF: 0.988 AC: 244116 AN: 247158 AF XY: 0.988

Gnomad AFR exome AF: 0.997

Gnomad AMR exome AF: 0.994

Gnomad ASJ exome AF: 0.996

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.973

Gnomad NFE exome AF: 0.983

Gnomad OTH exome AF: 0.988

GnomAD4 exome AF: 0.983 AC: 1436122 AN: 1460640 Hom.: 706059 Cov.: 39 AF XY: 0.984 AC XY: 714827 AN XY: 726568

African (AFR) AF: 0.997 AC: 33378 AN: 33464

American (AMR) AF: 0.994 AC: 44454 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 26021 AN: 26116

East Asian (EAS) AF: 1.00 AC: 39685 AN: 39696

South Asian (SAS) AF: 0.994 AC: 85676 AN: 86200

European-Finnish (FIN) AF: 0.973 AC: 51624 AN: 53068

Middle Eastern (MID) AF: 0.997 AC: 5747 AN: 5766

European-Non Finnish (NFE) AF: 0.981 AC: 1090142 AN: 1111304

Other (OTH) AF: 0.985 AC: 59395 AN: 60326

GnomAD4 genome AF: 0.988 AC: 150201 AN: 152082 Hom.: 74182 Cov.: 29 AF XY: 0.988 AC XY: 73399 AN XY: 74328

African (AFR) AF: 0.997 AC: 41343 AN: 41472

American (AMR) AF: 0.992 AC: 15173 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.994 AC: 3448 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5122 AN: 5124

South Asian (SAS) AF: 0.991 AC: 4773 AN: 4818

European-Finnish (FIN) AF: 0.970 AC: 10295 AN: 10610

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.982 AC: 66756 AN: 67980

Other (OTH) AF: 0.989 AC: 2085 AN: 2108

Alfa AF: 0.987 Hom.: 13609

Bravo AF: 0.990

Asia WGS AF: 0.998 AC: 3470 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.8
DANN	Benign	0.74
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9892013; hg19: chr17-62049235;