rs267604988

Variant names:

• chr17-63940878-C-T
• rs267604988
• NM_000334.4:c.5404G>A
• SCN4A p.Gly1802Arg

Your query was ambiguous. Multiple possible variants found:

• chr17-63940878-C-T
• chr17-63940878-C-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_000334.4(SCN4A):​c.5404G>A​(p.Gly1802Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1802E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: 0.209
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P
• paramyotonia congenita of Von Eulenburg

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Illumina, ClinGen
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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: Likely_benign. The variant received -4 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.055630475).
• BP6: Variant 17-63940878-C-T is Benign according to our data. Variant chr17-63940878-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 80615.

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.5404G>A	p.Gly1802Arg	missense	Exon 24 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.5404G>A	p.Gly1802Arg	missense	Exon 24 of 24	ENSP00000396320.1	P35499

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.0000281 AC: 7 AN: 248696 AF XY: 0.0000370

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461442 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 727024

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111844

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74484

African (AFR) AF: 0.000120 AC: 5 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hyperkalemic periodic paralysis (2)
-	2	-	not provided (2)
-	1	-	Congenital myasthenic syndrome 16 (1)
-	-	1	Hypokalemic periodic paralysis, type 2 (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	Paramyotonia congenita of Von Eulenburg (1)
-	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	Potassium-aggravated myotonia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	3.9
DANN	Benign	0.41
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.056	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.21
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.26
Sift	Benign	0.46	T
Sift4G	Benign	0.43	T
Varity_R		0.021
gMVP		0.23
Mutation Taster		=93/7	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs267604988;

hg19: chr17-62018238;