chr17-63941940-G-C

Variant names:

• chr17-63941940-G-C
• rs121908544
• NM_000334.4:c.4342C>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000334.4(SCN4A):​c.4342C>G​(p.Arg1448Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1448L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.02
• Publications: 0 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: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000334.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-63941939-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 586518.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 97 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 1.5606 (below the threshold of 3.09). Trascript score misZ: 2.2224 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital myasthenic syndrome 16, paramyotonia congenita of Von Eulenburg, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, type 2, congenital myopathy, hypokalemic periodic paralysis, SCN4A-related myopathy, autosomal recessive, congenital myopathy 22A, classic, potassium-aggravated myotonia, postsynaptic congenital myasthenic syndrome, myotonia fluctuans, myotonia permanens, acetazolamide-responsive myotonia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 17-63941940-G-C is Pathogenic according to our data. Variant chr17-63941940-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1451612.Status of the report is criteria_provided_single_submitter, 1 stars.

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.4342C>G	p.Arg1448Gly	missense	Exon 24 of 24	NP_000325.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4A	ENST00000435607.3	TSL:1 MANE Select	c.4342C>G	p.Arg1448Gly	missense	Exon 24 of 24	ENSP00000396320.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperkalemic periodic paralysis Pathogenic:1

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with autosomal dominant paramyotonia congenita (PMID: 32594687). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1448 of the SCN4A protein (p.Arg1448Gly). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 1451612). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Arg1448 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7676326, 8619545). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.89		Loss of MoRF binding (P = 0.0287)
MVP		0.97
MPC		0.97
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.95
gMVP		0.93
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs121908544; hg19: chr17-62019300;