NM_006514.4:c.4777A>T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_006514.4(SCN10A):c.4777A>T(p.Ile1593Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_006514.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN10A | ENST00000449082.3 | c.4777A>T | p.Ile1593Phe | missense_variant | Exon 28 of 28 | 1 | NM_006514.4 | ENSP00000390600.2 | ||
SCN10A | ENST00000643924.1 | c.4774A>T | p.Ile1592Phe | missense_variant | Exon 27 of 27 | ENSP00000495595.1 | ||||
SCN10A | ENST00000655275.1 | c.4801A>T | p.Ile1601Phe | missense_variant | Exon 28 of 28 | ENSP00000499510.1 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152104Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251246Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135774
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461880Hom.: 0 Cov.: 35 AF XY: 0.0000151 AC XY: 11AN XY: 727242
GnomAD4 genome AF: 0.0000592 AC: 9AN: 152104Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74296
ClinVar
Submissions by phenotype
Brugada syndrome 1 Uncertain:1
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Brugada syndrome Uncertain:1
This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1593 of the SCN10A protein (p.Ile1593Phe). This variant is present in population databases (rs762600386, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SCN10A-related conditions. ClinVar contains an entry for this variant (Variation ID: 532077). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SCN10A protein function with a negative predictive value of 80%. 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 Uncertain:1
The p.I1593F variant (also known as c.4777A>T), located in coding exon 27 of the SCN10A gene, results from an A to T substitution at nucleotide position 4777. The isoleucine at codon 1593 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at