17-63941922-G-A
Variant names:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
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).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
SCN4A
NM_000334.4 missense
NM_000334.4 missense
Scores
14
2
3
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
In a helix (size 12) in uniprot entity SCN4A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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: {Uncertain_significance=1, Likely_pathogenic=1, not_provided=1}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248644Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134818
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GnomAD4 exome AF: 0.00000892 AC: 13AN: 1457924Hom.: 0 Cov.: 35 AF XY: 0.00000828 AC XY: 6AN XY: 724520
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74372
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Congenital myasthenic syndrome 16 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 16, 2024 | - - |
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 | Jul 16, 2024 | - - |
Hyperkalemic periodic paralysis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 07, 2019 | 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). 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 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at L1452 (P = 0.0302);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at