rs80338792

Variant names:

• chr17-63943846-C-A
• rs80338792
• NM_000334.4:c.3917G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-63943846-C-A
• chr17-63943846-C-G
• chr17-63943846-C-T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000334.4(SCN4A):​c.3917G>T​(p.Gly1306Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000567468: Functional studies suggest that G1306V results in slower inactivation of the SCN4A sodium channel (Lerche et al., 1993)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1306E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 7.90
• Publications: 67 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet
• paramyotonia congenita of Von Eulenburg

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

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

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

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

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000567468: Functional studies suggest that G1306V results in slower inactivation of the SCN4A sodium channel (Lerche et al., 1993); PMID: 8308722; SCV000615092: Multiple studies indicate that this variant disrupts normal ion channel properties, resulting in aberrant channel regulation of current and signaling (PMID: 7473241, 16392038).; SCV000818060: Experimental studies have shown that this missense change affects SCN4A function (PMID: 7473241, 16392038).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr17-63943846-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 SCN4A-related myopathy, autosomal recessive, hyperkalemic periodic paralysis, paramyotonia congenita of Von Eulenburg, congenital myasthenic syndrome 16, acetazolamide-responsive myotonia, myotonia permanens, hypokalemic periodic paralysis, type 2, potassium-aggravated myotonia, congenital myopathy 22A, classic, congenital myopathy, myotonia fluctuans, postsynaptic congenital myasthenic syndrome, hypokalemic periodic paralysis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 17-63943846-C-A is Pathogenic according to our data. Variant chr17-63943846-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 5903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4A	NM_000334.4	MANE Select	c.3917G>T	p.Gly1306Val	missense	Exon 22 of 24	NP_000325.4	P35499

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4A	ENST00000435607.3	TSL:1 MANE Select	c.3917G>T	p.Gly1306Val	missense	Exon 22 of 24	ENSP00000396320.1	P35499

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249512 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449642 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 721982

African (AFR) AF: 0.00 AC: 0 AN: 33250

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 85980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1100932

Other (OTH) AF: 0.00 AC: 0 AN: 60004

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
3	-	-	Paramyotonia congenita of Von Eulenburg (3)
2	-	-	Hyperkalemic periodic paralysis (2)
2	-	-	Potassium-aggravated myotonia (2)
1	-	-	Paramyotonia congenita of Von Eulenburg;C0238357:Hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16;C5830453:Congenital myopathy 22A, classic;C5830501:Congenital myopathy 22B, severe fetal (1)
1	-	-	SCN4A-related disorder (1)
1	-	-	SCN4A-related non-dystrophic myotonia (1)
-	-	-	Paramyotonia congenita of Von Eulenburg;C0238357:Hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C5830453:Congenital myopathy 22A, classic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.80	P
Vest4		0.75
MutPred		0.81		Loss of disorder (P = 0.0258)
MVP		0.88
MPC		0.52
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.81
gMVP		0.64
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs80338792; hg19: chr17-62021206;