rs879253789

chr17-63941922-G-Achr17-63941922-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PP3_Strong PP5

The NM_000334.4(SCN4A):c.4360C>T(p.Arg1454Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,610,160 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1454Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: 0.771

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000334.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 17-63941922-G-A is Pathogenic according to our data. Variant chr17-63941922-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 243042.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4	c.4360C>T	p.Arg1454Trp	missense_variant	24/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3	c.4360C>T	p.Arg1454Trp	missense_variant	24/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 248644 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134818

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000892 AC: 13 AN: 1457924 Hom.: 0 Cov.: 35 AF XY: 0.00000828 AC XY: 6 AN XY: 724520

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000721

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myasthenic syndrome 16 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 14, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Experimental Epileptology, AG Lerche, Hertie Institute for Clinical Brain Research	May 07, 2022	The variant SCN4A:p.(R1454W) has been identified in compound heterozyous state with a previously unreported variant SCN4A:p.(N1205K). It has an extremely low frequency in gnomAD r2.1 (MAF = 0.00001609 and no homozygotes). It is located in the voltage sensor domain (S4) which is a mutational hotspot and multiple lines of computational evidence support a deleterious effect (CADD: 25.9, GERP++: 2.7, PPh2: 0.99, SIFT: 0). It was first reported in homozygous state in an individual who suffered from muscle weakness consistent with a diagnosis of autosomal recessive Congenital Myasthenic Syndrome 16 (MIM: #614198). Functional characterization in a heterologous expression system showed a net loss of funtion with enhanced fast and slow inactivation with slow recovery (PMID: 26659129). It was therefore classified as likely pathogenic (ACMG/AMP criteria: PS3, PM1, PM2, PP3). -

Congenital myopathy 22A, classic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 14, 2023

- -

Hyperkalemic periodic paralysis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has been reported to affect SCN4A protein function (PMID: 26659129). This variant has been observed in the homozygous state in an individual affected with congenital myasthenic syndrome who also experienced episodes of periodic paralysis (PMID: 26659129). ClinVar contains an entry for this variant (Variation ID: 243042). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 1454 of the SCN4A protein (p.Arg1454Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. -

Congenital myasthenic syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.047
FATHMM_MKL	Benign	0.38	N
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.1	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.77		Gain of catalytic residue at L1452 (P = 0.0302);
MVP		0.93
MPC		0.92
ClinPred		0.99	D
GERP RS		2.7
Varity_R		0.88
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs879253789; hg19: chr17-62019282; COSMIC: COSV71126808;