chr17-63964718-T-C

Variant names:

• chr17-63964718-T-C
• rs2877373
• NM_000334.4:c.1243-41A>G

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.1243-41A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.886 in 1,513,008 control chromosomes in the GnomAD database, including 598,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (51411 hom., cov: 32)
  • Exomes 𝑓: 0.89 (547390 hom.)
• Consequence: SCN4A NM_000334.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.254
• Publications: 7 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

LOC105371858 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-63964718-T-C is Benign according to our data. Variant chr17-63964718-T-C is described in ClinVar as Benign. ClinVar VariationId is 255843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.95 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4A	NM_000334.4	MANE Select	c.1243-41A>G		intron	N/A	NP_000325.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4A	ENST00000435607.3	TSL:1 MANE Select	c.1243-41A>G		intron	N/A	ENSP00000396320.1

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122715 AN: 152048 Hom.: 51395 Cov.: 32

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.954

Gnomad AMR AF: 0.890

Gnomad ASJ AF: 0.913

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.935

Gnomad FIN AF: 0.872

Gnomad MID AF: 0.905

Gnomad NFE AF: 0.901

Gnomad OTH AF: 0.831

GnomAD2 exomes AF: 0.893 AC: 158714 AN: 177688 AF XY: 0.900

Gnomad AFR exome AF: 0.541

Gnomad AMR exome AF: 0.934

Gnomad ASJ exome AF: 0.912

Gnomad EAS exome AF: 0.978

Gnomad FIN exome AF: 0.878

Gnomad NFE exome AF: 0.899

Gnomad OTH exome AF: 0.899

GnomAD4 exome AF: 0.895 AC: 1217720 AN: 1360842 Hom.: 547390 Cov.: 21 AF XY: 0.897 AC XY: 605875 AN XY: 675328

African (AFR) AF: 0.533 AC: 16591 AN: 31112

American (AMR) AF: 0.931 AC: 34414 AN: 36956

Ashkenazi Jewish (ASJ) AF: 0.913 AC: 22765 AN: 24938

East Asian (EAS) AF: 0.964 AC: 35405 AN: 36734

South Asian (SAS) AF: 0.930 AC: 73680 AN: 79206

European-Finnish (FIN) AF: 0.876 AC: 43075 AN: 49194

Middle Eastern (MID) AF: 0.904 AC: 3633 AN: 4020

European-Non Finnish (NFE) AF: 0.900 AC: 937596 AN: 1041760

Other (OTH) AF: 0.888 AC: 50561 AN: 56922

GnomAD4 genome AF: 0.807 AC: 122769 AN: 152166 Hom.: 51411 Cov.: 32 AF XY: 0.810 AC XY: 60291 AN XY: 74388

African (AFR) AF: 0.555 AC: 23037 AN: 41472

American (AMR) AF: 0.890 AC: 13615 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.913 AC: 3171 AN: 3472

East Asian (EAS) AF: 0.973 AC: 5032 AN: 5174

South Asian (SAS) AF: 0.935 AC: 4512 AN: 4826

European-Finnish (FIN) AF: 0.872 AC: 9242 AN: 10598

Middle Eastern (MID) AF: 0.905 AC: 266 AN: 294

European-Non Finnish (NFE) AF: 0.901 AC: 61264 AN: 68014

Other (OTH) AF: 0.833 AC: 1762 AN: 2116

Alfa AF: 0.847 Hom.: 7834

Bravo AF: 0.797

Asia WGS AF: 0.920 AC: 3198 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.3
DANN	Benign	0.38
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2877373; hg19: chr17-62042078;