rs116469710
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_000334.4(SCN4A):c.5499G>A(p.Glu1833=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,574,158 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0066 ( 18 hom., cov: 32)
Exomes 𝑓: 0.00062 ( 7 hom. )
Consequence
SCN4A
NM_000334.4 synonymous
NM_000334.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.947
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 -19 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.32).
BP6
Variant 17-63940783-C-T is Benign according to our data. Variant chr17-63940783-C-T is described in ClinVar as [Benign]. Clinvar id is 255859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.947 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00655 (998/152360) while in subpopulation AFR AF= 0.0228 (948/41588). AF 95% confidence interval is 0.0216. There are 18 homozygotes in gnomad4. There are 456 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 18 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| SCN4A | NM_000334.4 | c.5499G>A | p.Glu1833= | synonymous_variant | 24/24 | ENST00000435607.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SCN4A | ENST00000435607.3 | c.5499G>A | p.Glu1833= | synonymous_variant | 24/24 | 1 | NM_000334.4 | P1 |
Frequencies
GnomAD3 genomes 0.00656 AC: 998AN: 152242Hom.: 18 Cov.: 32
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GnomAD3 exomes AF: 0.00164 AC: 369AN: 224794Hom.: 8 AF XY: 0.00111 AC XY: 135AN XY: 121838
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GnomAD4 exome AF: 0.000616 AC: 876AN: 1421798Hom.: 7 Cov.: 30 AF XY: 0.000529 AC XY: 372AN XY: 702806
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GnomAD4 genome 0.00655 AC: 998AN: 152360Hom.: 18 Cov.: 32 AF XY: 0.00612 AC XY: 456AN XY: 74486
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ClinVar
Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 05, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Hyperkalemic periodic paralysis Benign:2
| Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Hypokalemic periodic paralysis, type 2 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Paramyotonia congenita of Von Eulenburg Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not provided Benign:1
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 14, 2018 | - - |
Potassium-aggravated myotonia Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Congenital myasthenic syndrome 16 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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