3-38752313-A-G
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_006514.4(SCN10A):āc.1661T>Cā(p.Leu554Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 1,610,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. L554I) has been classified as Uncertain significance.
Frequency
Consequence
NM_006514.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN10A | NM_006514.4 | c.1661T>C | p.Leu554Pro | missense_variant | 12/28 | ENST00000449082.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN10A | ENST00000449082.3 | c.1661T>C | p.Leu554Pro | missense_variant | 12/28 | 1 | NM_006514.4 | P4 | |
SCN10A | ENST00000655275.1 | c.1688T>C | p.Leu563Pro | missense_variant | 12/28 | ||||
SCN10A | ENST00000643924.1 | c.1661T>C | p.Leu554Pro | missense_variant | 11/27 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000987 AC: 15AN: 151998Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000928 AC: 23AN: 247808Hom.: 0 AF XY: 0.0000970 AC XY: 13AN XY: 133970
GnomAD4 exome AF: 0.0000555 AC: 81AN: 1458858Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 39AN XY: 725694
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74384
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 29, 2020 | This variant is associated with the following publications: (PMID: 23115331, 24006052, 24820863, 23986244, 25060923, 24763188) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2016 | - - |
Episodic pain syndrome, familial, 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 20, 2012 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 28, 2022 | Variant summary: SCN10A c.1661T>C (p.Leu554Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.3e-05 in 247808 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SCN10A causing SCN10A-Related Disorders, allowing no conclusion about variant significance. c.1661T>C has been reported in the literature in individuals affected with SCN10A-Related Disorders. This report does not provide unequivocal conclusions about association of the variant with SCN10A-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function and showed L554 affected sodium channel function. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=2, likely benign n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 21, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 554 of the SCN10A protein (p.Leu554Pro). This variant is present in population databases (rs138404783, gnomAD 0.02%). This missense change has been observed in individual(s) with neuropathy (PMID: 23115331). ClinVar contains an entry for this variant (Variation ID: 89014). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCN10A protein function. Experimental studies have shown that this missense change affects SCN10A function (PMID: 23115331). 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. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 24, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at