rs115695396
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PP3_StrongBP6_Very_StrongBA1
The NM_000334.4(SCN4A):c.2989+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00349 in 1,569,074 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.019 ( 105 hom., cov: 33)
Exomes 𝑓: 0.0018 ( 89 hom. )
Consequence
SCN4A
NM_000334.4 splice_donor_5th_base, intron
NM_000334.4 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.25
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 -12 ACMG points.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
BP6
Variant 17-63949388-C-T is Benign according to our data. Variant chr17-63949388-C-T is described in ClinVar as [Benign]. Clinvar id is 130231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0637 is higher than 0.05.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SCN4A | NM_000334.4 | c.2989+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000435607.3 | NP_000325.4 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN4A | ENST00000435607.3 | c.2989+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_000334.4 | ENSP00000396320 | P1 | |||
| SCN4A | ENST00000584310.1 | n.312+5G>A | splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes 0.0190 AC: 2885AN: 152156Hom.: 105 Cov.: 33
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GnomAD3 exomes AF: 0.00403 AC: 724AN: 179700Hom.: 28 AF XY: 0.00319 AC XY: 309AN XY: 96722
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GnomAD4 exome AF: 0.00182 AC: 2585AN: 1416800Hom.: 89 Cov.: 31 AF XY: 0.00154 AC XY: 1082AN XY: 700874
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GnomAD4 genome 0.0189 AC: 2884AN: 152274Hom.: 105 Cov.: 33 AF XY: 0.0180 AC XY: 1343AN XY: 74444
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ClinVar
Significance: Benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2016 | 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. - |
| Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | - | Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. - |
Familial hyperkalemic periodic paralysis Benign:2
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | - - |
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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 13, 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 13, 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;C0238357:Familial hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 31, 2017 | - - |
not provided Benign:1
| Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Potassium-aggravated myotonia Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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 13, 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
Source:
Name
Calibrated prediction
Score
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at