rs544082594
Positions:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1
The NM_000334.4(SCN4A):āc.3004T>Cā(p.Trp1002Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,609,060 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00011 ( 0 hom., cov: 33)
Exomes š: 0.00012 ( 1 hom. )
Consequence
SCN4A
NM_000334.4 missense
NM_000334.4 missense
Scores
4
5
10
Clinical Significance
Conservation
PhyloP100: 8.33
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 Benign. Variant got -7 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.06986666).
BP6
?
Variant 17-63948751-A-G is Benign according to our data. Variant chr17-63948751-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 579545.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000105 (16/152344) while in subpopulation SAS AF= 0.00248 (12/4830). AF 95% confidence interval is 0.00143. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN4A | NM_000334.4 | c.3004T>C | p.Trp1002Arg | missense_variant | 16/24 | ENST00000435607.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN4A | ENST00000435607.3 | c.3004T>C | p.Trp1002Arg | missense_variant | 16/24 | 1 | NM_000334.4 | P1 | |
SCN4A | ENST00000584310.1 | n.327T>C | non_coding_transcript_exon_variant | 2/3 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000985 AC: 15AN: 152226Hom.: 0 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000342 AC: 84AN: 245464Hom.: 0 AF XY: 0.000345 AC XY: 46AN XY: 133270
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GnomAD4 exome AF: 0.000125 AC: 182AN: 1456716Hom.: 1 Cov.: 31 AF XY: 0.000153 AC XY: 111AN XY: 724032
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GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152344Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74490
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 08, 2024 | Reported in the homozygous state in a patient with microcephaly and spasticity in published literature (PMID: 31069529); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31069529) - |
Paramyotonia congenita of Von Eulenburg;C0238357:Hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16;C3714580:Hypokalemic periodic paralysis, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 29, 2021 | - - |
Hyperkalemic periodic paralysis Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of disorder (P = 0.0155);
MVP
MPC
ClinPred
T
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