chr3-38581065-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PP2BP4_StrongBP6
The NM_001099404.2(SCN5A):c.3094G>A(p.Glu1032Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. E1032D) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.3094G>A | p.Glu1032Lys | missense_variant | 17/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.3094G>A | p.Glu1032Lys | missense_variant | 17/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.3094G>A | p.Glu1032Lys | missense_variant | 17/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.3094G>A | p.Glu1032Lys | missense_variant | 17/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152108Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000443 AC: 11AN: 248578Hom.: 0 AF XY: 0.0000371 AC XY: 5AN XY: 134928
GnomAD4 exome AF: 0.0000493 AC: 72AN: 1461654Hom.: 0 Cov.: 37 AF XY: 0.0000550 AC XY: 40AN XY: 727104
GnomAD4 genome AF: 0.0000592 AC: 9AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74298
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 18, 2012 | The Glu1032Lys variant in the SCN5A gene has been reported previously in one patient with an unspecified arrhythmia (Oliva Sandoval MJ et al., 2011). Although Glu1032Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic Acid with a positively charged Lysine, this substitution occurs at a position that is not well conserved across species. Consequently, in silico analysis predicts Glu1032Lys has a benign effect on the protein structure/function. One nearby mutation (Gln1033Arg) has been reported in association with LQTS. The Glu1032Lys variant was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project.With the clinical and molecular information available at this time, we cannot definitively determine if Glu1032Lys is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1032 of the SCN5A protein (p.Glu1032Lys). This variant is present in population databases (rs369565476, gnomAD 0.01%). This missense change has been observed in individual(s) with long QT syndrome and/or other SCN5A-related conditions (PMID: 26669661, 30847666). ClinVar contains an entry for this variant (Variation ID: 201490). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Cardiac arrhythmia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 09, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at